Substituted azetidiones as anti-inflammatory and antidegenerative agents

ABSTRACT

Substituted azetidinones are herein disclosed for use in the treatment of various elastase-mediated diseases.

RELATED APPLICATION DATA

This is a continuation of application Ser. No. 08/416,771 filed on Apr.13, 1995, abandoned. This is a National Filing of Internationalapplication number PCT/US93/10268 filed Oct. 26, 1993.

BACKGROUND OF THE INVENTION

We have found that a group of new substituted azetidinones are potentelastase inhibitors and therefore are useful anti-inflammatory andantidegenerative agents.

Proteases from granulocytes and macrophages have been reported to beresponsible for the chronic tissue destruction mechanisms associatedwith inflammation, including rheumatoid arthritis and emphysema.Accordingly, specific and selective inhibitors of these proteases arecandidates for potent anti-inflammatory agents useful in the treatmentof inflammatory conditions resulting in connective tissue destruction,e.g. rheumatoid arthritis, emphysema, bronchial inflammation, chronicbronchitis, glomerulonephritis, osteoarthritis, spondylitis, lupus,psoriasis, atherosclerosis, sepsis, septicemia, shock, myocardialinfarction, reperfusion injury, periodontitis, cystic fibrosis and acuterespiratory distress syndrome.

The role of proteases from granulocytes, leukocytes or macrophages arerelated to a rapid series of events which occurs during the progressionof an inflammatory condition:

(1) There is a rapid production of prostaglandins (PG) and relatedcompounds synthesized from arachidonic acid. This PG synthesis has beenshown to be inhibited by aspirin-related nonsteroidal anti-inflammatoryagents including indomethacin and phenylbutazone. There is some evidencethat protease inhibitors prevent PG production;

(2) There is also a change in vascular permeability which causes aleakage of fluid into the inflamed site and the resulting edema isgenerally used as a marker for measuring the degree of inflammation.This process has been found to be induced by the proteolytic or peptidecleaving activity of proteases, especially those contained in thegranulocyte, and thereby can be inhibited by various synthetic proteaseinhibitors, for example, N-acyl benzisothiazolones and the respective1,1-dioxides. Morris Zimmerman et al., J. Biol. Chem., 255, 9848 (1980);and

(3) There is an appearance and/or presence of lymphoid cells, especiallymacrophages and polymorphonuclear leukocytes (PMN). It has been knownthat a variety of proteases are released from the macrophages and PMN,further indicating that the proteases do play an important role ininflammation.

In general, proteases are an important family of enzymes within thepeptide bond cleaving enzymes whose members are essential to a varietyof normal biological activities, such as digestion, formation anddissolution of blood clots, the formation of active forms of hormones,the immune reaction to foreign cells and organisms, etc., and inpathological conditions such as the degradation of structural proteinsat the articular cartilage/pannus junction in rheumatoid arthritis etc.

Elastase is one of the proteases. It is an enzyme capable of hydrolyzingthe connective tissue component elastin, a property not contained by thebulk of the proteases present in mammals. It acts on a protein'snonterminal bonds which are adjacent to an aliphatic amino acid.Neutrophil elastase is of particular interest because it has thebroadest spectrum of activity against natural connective tissuesubstrates. In particular, the elastase of the granulocyte is importantbecause, as described above, granulocytes participate in acuteinflammation and in acute exacerbation of chronic forms of inflammationwhich characterize many clinically important inflammatory diseases.

Proteases may be inactivated by inhibitors which block the active siteof the enzyme by binding tightly thereto. Naturally occurring proteaseinhibitors form part of the control or defense mechanisms that arecrucial to the well-being of an organism. Without these controlmechanisms, the proteases would destroy any protein within reach. Thenaturally occurring enzyme inhibitors have been shown to haveappropriate configurations which allow them to bind tightly to theenzyme. This configuration is part of the reason that inhibitors bind tothe enzyme so tightly (see Stroud, "A Family of Protein-CuttingProteins" Sci. Am. Jul. 1974, pp. 74-88). For example, one of thenatural inhibitors, α₁ -Antitrypsin, is a glycoprotein contained inhuman serum that has a wide inhibitory spectrum covering, among otherenzymes, elastase both from the pancreas and the PMN. This inhibitor ishydrolyzed by the proteases to form a stable acyl enzyme in which theactive site is no longer available. Marked reduction in serum α₁-antitrypsin, either genetic or due to oxidants, has been associatedwith pulmonary emphysema which is a disease characterized by aprogressive loss of lung elasticity and resulting respiratorydifficulty. It has been reported that this loss of lung elasticity iscaused by the progressive, uncontrolled proteolysis or destruction ofthe structure of lung tissue by proteases such as elastase released fromleukocytes. J. C. Powers, TIBS, 211 (1976).

Rheumatoid arthritis is characterized by a progressive destruction ofarticular cartilage both on the free surface bordering the joint spaceand at the erosion front built up by synovial tissue toward thecartilage. This destruction process, in turn, is attributed to theprotein-cutting enzyme elastase which is a neutral protease present inhuman granulocytes. This conclusion has been supported by the followingobservations:

(1) Recent histochemical investigations showed the accumulation ofgranulocytes at the cartilage/ pannus junction in rheumatoid arthritis;and

(2) a recent investigation of mechanical behavior of cartilage inresponse to attack by purified elastase demonstrated the directparticipation of granulocyte enzymes, especially elastase, in rheumatoidcartilage destruction. H. Menninger et al., in Biological Functions ofProteinases, E. Holzer and H. Tschesche, eds. Springer-Verlag, Berlin,Heidelberg, New York, pp. 196-206, 1979.

In a second aspect this invention concerns the use of novel azetidinonesin the treatment of certain cancers including nonlymphoblasticleukemias, acute myelogenous leukemia (FAB M1 and FAB M2), acutepromyelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4),acute monocytic leukemia (FAB M5), erythroleukemia, chronic myelogenousleukemia, chronic myelomonocytic leukemia, chronic monocytic leukemiaand conditions associated with leukemia involving activity of PMNneutral proteases e.g. disseminated intravascular coagulation. We havefound that the substituted azetidinones disclosed herein are inhibitorsof proteinase 3 (PR-3), also known as myeloblastin.

See C. Labbaye, et al., Proc. Natl. Acad. Sci. USA, vol. 88, 9253-9256,(1991), Wegner autoantigen and myeloblastin are encoded by a singlemRNA; D. Campanelli, et al., J. Exp. Med., vol. 172, 1709-1714, (1990),Cloning of cDNA for proteinase 3: A serine protease, antibiotic, andautoantigen from human neutrophils; and Bories, et. al., Cell vol. 59,959-968, (1989) Down-regulation of a serine protease, myeloblastin,causes growth arrest and differentiation of promyelocytic leukemiacells.

Recently, down regulation of PR-3 has been implicated in theproliferation and maintenance of a differentiated state of certainleukemia cells. In particular, Bories, et. al., have shown thatexpression of this enzyme, hereinafter designated proteinase3/myeloblastin, can be inhibited by treatment of HL-60 human leukemiacells with an antisense oligodeoxynucleotide and that such treatmentinduces differentiation and inhibits proliferation of these cells.Moreover, we have now demonstrated that the treatment of the HL-60 cellhuman leukemia cell line, among others, with the compounds of theinstant invention, likewise results in the inhibition of proliferationand induction of differentiation in such cells.

Accordingly, we believe that treatment of leukemia such asnonlymphoblastic leukemias, acute myelogenous leukemia (FAB M1 and FABM2), acute promyelocytic leukemia (FAB M3), acute myelomonocyticleukemia (FAB M4), acute monocytic leukemia (FAB M5), erythroleukemia,chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronicmonocytic leukemia and conditions associated with leukemia involvingactivity of PMN neutral proteases e.g. disseminated intravascularcoagulation, comprising: administration of a therapeutically effectiveamount of compound of Formula I will result in remission of the diseasestate. Administration may be either oral or parenteral.

BRIEF DESCRIPTION OF THE INVENTION

The instantly claimed invention is directed to specifically substitutedazetidinones of Formula I ##STR1##

These substituted azetidinones have been found to be usefulanti-inflammatory and antidegenerative agents. This invention is alsodirected to pharmaceutical compositions and methods of using thesespecifically substituted azetidinones. These compounds will also beuseful in the treatment of certain leukemias and leukemia relatedconditions.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to potent elastase inhibitors of Formula (I),##STR2## which are useful in the prevention, control and treatment ofinflammatory and degenerative conditions especially arthritis andemphysema.

More particularly, the instant invention is directed to the compounds ofthe Formula (I) ##STR3## and pharmaceutically acceptable salts thereofwherein: R is C₁₋₆ alkyl;

R¹ is C₁₋₆ alkyl or C₁₋₆ alkoxy-C₁₋₆ alkyl;

M is

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) hydroxy C₁₋₆ alkyl,

(4) halo C₁₋₆ alkyl,

(5) C₂₋₆ alkenyl, or

(6) C₁₋₆ alkoxy-C₁₋₆ alkyl;

Ra and Rb are each individually

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) halo,

(4) carboxy,

(5) C₁₋₆ alkoxy,

(6) phenyl,

(7) C₁₋₆ alkylcarbonyl,

(8) di-(C₁₋₆ alkyl)amino;

(9) hydroxy;

R² and R³ are each independently

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) halo,

(4) carboxy,

(5) C₁₋₆ alkoxy,

(6) phenyl,

(7) C₁₋₆ alkylcarbonyl,

(8) aminoC₂₋₃ alkyloxy carbonyl wherein the amino is optionally mono ordi substituted with C₁₋₆ alkyl,

(9) aminoC₂₋₃ alkylamino carbonyl wherein the amino is optionally monoor di substituted with C₁₋₆ alkyl,

(10) hydroxy,

(11) aminocarbonyl wherein the amino is optionally mono or disubstituted with C₁₋₆ alkyl,

(12) hydroxymethyl,

(13) aminocarbonyloxy C₁₋₃ alkyloxy wherein the amino is optionally monoor di substituted with C₁₋₆ alkyl,

(14) cyano,

(15) morpholinocarbonylphenyl,

(16) amino wherein the amino is optionally mono or di substituted withC₁₋₆ alkyl, with the proviso that R² and R³ may be joined together toform a methylenedioxy group or a furan ring,

(17) morpholinocarbonyl; ##STR4## wgere R_(x) is carboxybenzyloxycarbonylC₁₋₃ alkyl, or

t-butoxycarbonylC₁₋₃ alkyl,

wherein

Q is a covalent bond or ##STR5## wherein R₅ and R₆ are each individuallyC₁₋₃ alkyl or hydrogen, ##STR6## or a covalent bond; R₁₂ is hydrogen orC₁₋₃ alkyl;

R₇ and R₈ are each individually

(a) hydrogen,

(b) C₁₋₆ alkyl,

(c) C₁₋₆ alkyloxy C₂₋₃ alkyl,

(d) hydroxy C₂₋₆ alkyl,

(e) polyhydroxyC₂₋₆ alkyl,

(f) carboxamido C₁₋₆ alkyl,

(g) polyacyloxyC₂₋₆ alkyl

(h) C₁₋₆ alkanoyl,

(i) substituted phenyl or phenyl C₁₋₆ alkyl, wherein the substitutent isX₁ as defined immediately below,

(j) C₂₋₆ alkenyl,

(k) C₆₋₁₀ cycloalkenyl,

(1) heteroaryl C₁₋₆ alkyl wherein the hetero aryl includes pyridinyl,imidazolyl, triazolyl, benzylimidazolyl, and furyl,

(m) carboxy C₁₋₆ alkyl,

(n) carbo C₁₋₆ alkoxy C₁₋₃ alkyl,

(o) phenylsulfonyl,

(p) C₁₋₆ alkylsulfonyl,

(q) benzyloxy,

(r) morpholinyl C₁₋₃ alkylsulfonyl,

(s) tetrahydropyranyl,

(t) aminoC₁₋₃ alkylsulfonyl wherein the amino is optionally mono or disubstituted with C₁₋₆ alkyl,

(u) aminocarbonyl wherein the amino is optionally mono or di substitutedwith C₁₋₆ alkyl,

(v) aminocarbonyloxyC₂₋₆ alkyl wherein the amino is optionally mono ordi substituted with C₁₋₆ alkyl,

(w) azabicyclo of 7 to 12 atoms,

(x) di C₁₋₃ alkylamino C₂₋₆ alkyl wherein the amino is optionally monoor di substituted with C₁₋₆ alkyl,

(y) bicycloalkyl of 7 to 12 atoms,

(z) C₃₋₁₀ cycloalkyl optionally substituted with C₁₋₆ alkyl,

(aa) pyrazolidinyl,

(bb) substituted piperidinyl or prrrolidinyl wherein the substitutent ishydrogen, C₁₋₃ alkyl, hydroxyC₁₋₃ alkylbenzyl, carboxamido or aminowherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(cc) substituted pyrrolidinyl wherein the substitutent is carboxamido oramino wherein the amino is optionally mono or di substituted with C₁₋₆alkyl,

(dd) pyrimidinyl,

(ee) N-cyano-N'-phenylamidino,

(ff) phosphonoC₁₋₆ alkyl, or

(gg) α-C₁₋₃ alkyl benzyl or mono or di substituted benzyl or mono or disubstituted pyridylmethyl, wherein the substitutents are X₁ and X₂,

wherein

X₁ is

(1) hydrogen,

(2) halo,

(3) C₁₋₆ alkyl,

(4) halo-C₁₋₆ alkyl,

(5) C₂₋₆ alkenyl,

(6) hydroxy-C₁₋₆ alkyl,

(7) C₁₋₆ alkylcarbonyl,

(8) C₁₋₆ alkylcarbonylamino;

(9) CN,

(10) CF₃,

(11) CH₃ O,

(12) amino wherein the amino is optionally mono or di substituted withC₁₋₆ alkyl;

(13) carboxy, or

(14) phenylsulfonylaminocarbonyl;

X₂ is hydrogen, halo or C₁₋₆ alkyl;

n is 1, 2, 3, 4 or 5;

R₉ is selected from hydrogen, C₁₄ alkyl, and C₁₋₃ alkoxyC₁₋₃ alkyl; orphenyl, phenyl C₁₋₃ alkyl, pyridyl, and pyridyl C₁₋₃ alkyl;

R₁₀ and R₁₁ are each independently selected from hydrogen, C₁₋₄ alkyl,and C₁₋₃ alkoxy C₁₋₃ alkyl, or aryl as defined above, or are togetherO═; or

wherein R₇ and R₈ are joined together to form mono or di substitutedring of 4, 5, 6, or 7 atoms or 7 to 12 atoms such as

(1) piperidinyl or homopiperdinyl,

(2) piperazinyl,

(3) morpholinyl, thiomorpholinyl or

1,1-dioxo-4-thiomorpholinyl,

(4) pyrroylidinyl,

(5) pyrryl,

(6) imidazolyl,

(7) triazolyl,

(8) saturated azabicyclo of 7 to 12 atoms,

(9) azaspiro having 3 to 9 carbon atoms, said ring being saturated,

(10) tetrazolyl,

(11) pyrazolidinyl,

(12) dihydodimethozyisoquinolyl,

(13) azetidinyl, or

(14) diazabicyclo ring of 7-12 atoms,

wherein the substituents are each selected from the group consisting ofhydrogen and C₁₋₃ alkyl, benzyloxycarbonyl, carboxy, phenyl C₁₋₃ alkylamino carbonyl, pyrrolidinylmethyl, hydroxy C₁₋₃ alkyl, C₁₋₆ alkyloxy,C₁₋₄ alkyloxy carbonyl, aminocarbonyl wherein the amino is optionallymono or di substituted with C₁₋₆ alkyl, and oxo; or

--N(R7)R8 may be an amino acid residue including natural amino acidssuch as lysine; or R₈ and R₉ are joined together to form a mono or disubstituted saturated monocyclic ring of 6 to 7 atoms and having twohetero atoms which are the nitrogens to which R₈ and R₉ are attached;said rings to include piperazinyl and homopiperazinyl; or R₉ and R₁₀ arejoined together to form a mono or di substituted monocyclic saturatedring of 5 to 7 atoms and having one hetero atom which is the nitrogen towhich R₉ is attached; or

wherein R₉ and R₁₂ are joined together to form a mono or di substitutedsaturated monocyclic ring of 5, 6; or 7 atoms, said ring having onehetero atom which is the nitrogen to which R₉ is attached; or whereinR₁₀ and R₁₂ are joined together to form a mono or di substitutedsaturated monocyclic ring of 5, 6, or 7 carbon atoms; or

wherein R₈ and R₁₁ are joined together to form a mono or di substitutedsaturated monocyclic ring of 5, 6, or 7 atoms, said ring having onehetero atom which is the nitrogen to which R₈ is attached; and thesubstituents are independently selected from Hydrogen and C1-3alkyl.

As appreciated by those of Skill in the art the term "alkyl" such as inC₁₋₆ alkyl, includes, methyl, ethyl, propyl, butyl, pentyl, and hexyl,and where appropriate, branched chained forms including isopropyl andtert-butyl.

As may also be appreciated by those of skill in the art, the ##STR7##spacer in definition Y, may, in the alternative be placed to the rightof CR₁₀ R₁₁.

As may also be appreciated, the group ##STR8## may also be oxidized tothe corresponding oxide

In one Class the instant invention is directed to the compounds of theFormula (I) ##STR9## and pharmaceutically acceptable salts thereofwherein: R is C₁₋₆ alkyl;

R¹ is C₁₋₆ alkyl or C₁₋₆ alkoxy-C₁₋₆ alkyl;

M is

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) hydroxy C₁₋₆ alkyl,

(4) halo C₁₋₆ alkyl,

(5) C₂₋₆ alkenyl, or

(6) C₁₋₆ alkoxy-C₁₋₆ alkyl;

Ra is

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) halo,

(4) carboxy,

(5) C₁₋₆ alkoxy,

(6) phenyl,

(7) C₁₋₆ alkylcarbonyl,

(8) amino wherein the amino is optionally mono or di substituted withC₁₋₆ alkyl;

Rb is hydrogen, or C₁₋₆ alkyl,

R² and R³ are each independently

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) halo,

(4) carboxy,

(5) C₁₋₆ alkoxy,

(6) phenyl,

(7) C₁₋₆ alkylcarbonyl,

(8) amino wherein the amino is optionally mono or di substituted withC₁₋₆ alkyl, or with the proviso that R² and R³ may be joined together toform a methylenedioxy group or a furan ring; ##STR10## where R_(x) iscarboxyC₁₋₆ alkyl, benzyloxycarbonylC₁₋₃ alkyl, or

t-butoxycarbonylC₁₋₃ alkyl,

wherein

Q is a covalent bond or ##STR11## wherein R₅ and R₆ are eachindividually C₁₋₃ alkyl or hydrogen ##STR12## or a covalent bond; R₁₂ ishydrogen or C₁₋₃ alkyl;

R₇ and R₈ are each individually

(a) hydrogen,

(b) C₁₋₆ alkyl,

(c) C₁₋₆ alkyloxy C₂₋₃ alkyl,

(d) hydroxy C₂₋₆ alkyl,

(e) carboxamido C₁₋₆ alkyl,

(f) C₁₋₆ alkanoyl,

(g) substituted phenyl or phenyl C₁₋₆ alkyl wherein the substitutentsare X₁, and X₂

(h) C₂₋₆ alkenyl,

(i) C₆₋₁₀ cycloalkenyl,

(j) heteroaryl C₁₋₆ alkyl wherein the hetero aryl includes pyridinyl,imidazolyl, triazolyl, benzylimidazolyl, and furyl,

(k) carboxy C₁₋₆ alkyl,

(l) C₁₋₆ alkylsulfonyl,

(m) carboC₁₋₆ alkyloxyC₂₋₃ alkyl,

(n) morpholinyl C₁₋₃ alkylsulfonyl,

(o) aminoC₁₋₃ alkylsulfonyl wherein the amino is optionally mono or disubstituted with C₁₋₆ alkyl,

(p) aminocarbonyl wherein the amino is optionally mono or di substitutedwith C₁₋₆ alkyl,

(q) aminocarbonyloxyC₁₋₆ alkyl wherein the amino is optionally mono ordi substituted with C₁₋₆ alkyl,

(r) di C₁₋₃ alkylamino C₁₋₆ alkyl wherein the amino is optionally monoor di substituted with C₁₋₆ alkyl,

(s) pyrazolidinyl,

(t) substituted piperidinyl as defined above,

(u) substituted pyrrolidinyl as defined above,

(v) pyrimidinyl,

(w) benzyloxy,

(x) C₃₋₁₀ cycloalkyl,

(z) α-C₁₋₃ alkyl benzyl or mono or di substituted benzyl or mono or disubstituted pyridylmethyl, wherein the substitutents are X₁ and X₂,

wherein

X₁ is

(1) hydrogen,

(2) halo,

(3) C₁₋₆ alkyl,

(4) halo-C₁₋₆ alkyl,

(5) C₂₋₆ alkenyl,

(6) hydroxy-C₁₋₆ alkyl,

(7) C₁₋₆ alkylcarbonyl,

(8) C₁₋₆ alkylcarbonylamino;

(9) di-C₁₋₃ alkylamino; or

(10) carboxy,

X₂ is hydrogen, halo or C₁₋₆ alkyl;

n is 1, 2, 3, 4 or 5;

R₉ is selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxyC₁₋₃ alkyl; R₁₀and R₁₁ are each independently selected from hydrogen, C₁₋₄ alkyl, andC₁₋₃ alkoxy C₁₋₃ alkyl; or

wherein R₇ and R₈ are joined together to form mono or di substitutedring of 4, 5, 6, or 7 atoms such as

(1) piperidinyl,

(2) piperazinyl,

(3) morpholinyl,

(4) pyrroylidinyl,

(5) pyrryl,

(6) imidazolyl,

(7) triazolyl,

(8) tetrazolyl,

(9) pyrazolidinyl,

(10) azetidinyl,

wherein the substituents are each selected from the group consisting ofhydrogen and C₁₋₃ alkyl, benzyloxycarbonyl, carboxy, phenyl C₁₋₃ alkylamino carbonyl, pyrrolidinyl, methyl, hydroxy C₁₋₃ alkyl, C₁₋₆ alkyloxy,C₁₋₄ alkyloxy carbonyl, and oxo; or R₈ and R₉ are joined together toform a saturated ring of 5 to 7 atoms and having two hetero atoms; or R₉and R₁₀ are joined together to form a saturated ring of 5 to 7 atoms andhaving one hetero atom; or wherein R₉ and R₁₂ are joined together toform a ring of 5, 6, or 7 atoms, said ring being saturated; or whereinR₁₀ and R₁₂ are joined together to form a ring of 5, 6, or 7 atoms, saidring being saturated; or

wherein R₈ and R₁₁ are joined together to form a ring of 5, 6, or 7atoms, said ring being saturated and having one hetero atom.

In one subclass, the invention concerns compounds of Formula I wherein

R is C₁₋₃ alkyl;

R₁ is C₁₋₃ alkyl;

M is

(a) C₁₋₆ alkyl, or

(b) C₂₋₆ alkenyl;

R² is

(a) hydrogen,

(b) C₁₋₆ alkyl, or C₁₋₆ alkoxy, and

R³ is hydrogen, or R² and R³ are joined together to form amethylenedioxy group or a furan ring;

R₅ and R₆ are each individually hydrogen or C₁₋₃ alkyl;

R₇ and R₈ are each independently selected from

(a) hydrogen,

(b) C₁₋₃ alkyl,

(c) C₁₋₃ alkoxy C₂₋₃ alkyl,

(d) C₃₋₇ cycloalkyl,

(e) hydroxyC₂₋₃ alkyl,

(d) carbo C₁₋₄ alkyloxymethyl,

(g) substituted benzyl wherein the substituents are X₁ and X₂

wherein X₁ is hydrogen and X₂ is

(1) hydrogen,

(2) halo, or

(3) C₁₋₃ alkyl;

n is 1, 2 or 3, and

R₉, R₁₀ and R₁₁ are each independently selected from hydrogen, C₁₋₄alkyl, and C₁₋₃ alkoxy C₁₋₃ alkyl; or

R₇ and R₈ are joined together to form a substituted ring selected from

(a) piperidinyl,

(b) piperazinyl, and

(c) morpholinyl;

or

R₈ and R₉ are joined together to form a ring of 6 to

7 atoms and having two hetero atoms; R₉ and R₁₀ are joined together toform a saturated ring of 5 to 7 atoms and having one hetero atom; orwherein R₉ and R₁₂ are joined together to form a ring of 5, 6, or 7atoms, said ring being saturated; or wherein R₁₀ and R₁₂ are joinedtogether to form a ring of 5, 6, or 7 atoms, said ring being saturated;or

wherein R₈ and R₁₁ are joined together to form a ring of 5, 6, or 7atoms, said ring being saturated and having one hetero atom.

In a narrower sub-class are the compounds wherein

Q is a covalent bond;

R is methyl or ethyl;

R₁ is methyl or ethyl;

M is

(a) C₁₋₄ alkyl, or

(b) C₂₋₃ alkenyl;

R² is

(a) hydrogen,

(b) C₁₋₃ alkyl, or C₁₋₃ alkoxy, and

R³ is hydrogen, or

R² and R³ are joined together to form a furan or dioxacyclopentane ring;

n is 1 or 2;

R₉ and R₁₀ are each independently selected from

(a) C₁₋₃ alkyl,

(b) C₁₋₃ alkoxy C₁₋₃ alkyl,

(c) hydrogen,

R₇ and R₈ are each independently selected from

(a) C₁₋₃ alkyl,

(b) C₁₋₃ alkoxy C₂₋₃ alkyl,

(c) hydrogen,

(d) hydroxyethyl,

(e) carboethoxymethyl,

(f) cyclopropyl,

or

R₇ and R₈ are joined together to form a substituted ring selected from

(a) piperidinyl, and

(b) morpholinyl, or

R₈ and R₉ are joined together to form a piperazine ring.

As is defined above, various rings are formed when R8, R9, R10 and R12are joined. The following is a non-limiting description of some of thepreferred rings that are formed when these various substituents arejoined.

R8 and R9 are joined ##STR13## R9 and R10 are joined ##STR14## R9 andR12 are joined ##STR15## R10 and R12 are joined ##STR16## R10 and R12are joined ##STR17##

In another aspect the present invention is directed to the treatment ofleukemia, such as nonlymphoblastic leukemias, acute myelogenous leukemia(FAB M1 and FAB M2), acute promyelocytic leukemia (FAB M3), acutemyelomonocytic leukemia (FAB M4), acute monocytic leukemia (FAB M5),erythroleukemia, chronic myelogenous leukemia, chronic myelomonocyticleukemia, chronic monocytic leukemia and conditions associated withleukemia involving activity of PMN neutral proteases e.g. disseminatedintravascular coagulation with compounds of Formula I.

Treatment of leukemia cells comprises: administration of atherapeutically effective amount of a compound of Formula I results inthe inhibition of proteinase 3/myeloblastin, inhibition of elastase,inhibition of proliferation of the leukemia cells, induction ofdifferentiation of the leukemia cells, and remission of the diseasestate.

In one alternative embodiment the invention concerns a method oftreating leukemia comprising:

administration to a patient in need of such treatment of atherapeutically effective amount of compound of Formula I.

In a second alternative embodiment the invention concerns a method ofinhibiting proteinase 3/myeloblastin, comprising:

administration to a patient in need of such inhibition of atherapeutically effective amount of compound of Formula I as definedabove.

In a third alternative embodiment the invention concerns a method ofinhibiting proteinase 3/myeloblastin and elastase, comprising:

administration to a patient in need of such inhibition of atherapeutically effective amount of compound of Formula I as or apharmaceutically acceptable salt thereof as defined above.

In a fourth embodiment the invention concerns a method of inducingcellular differentiation in leukemia cells comprising:

administration to a patient in need of such inhibition of atherapeutically effective amount of compound of Formula I or apharmaceutically acceptable salt thereof as defined above.

Each of the above alternative embodiments (i.e., those relating to PR3or cancer), also concerns co-administration of a compound of Formula Ias defined above, with an agent or agents known in the art for treatmentof leukemia, including, but not limited to epsilon-aminocaproic acid,heparin, trasylol (aprotinin); prednisolone; cytosine arabinoside;β-mercaptopurine; cytarabine; an anthracycline (see Young et. al. (1981)N. Engl. J. Med. 305:139) such as daunorubicin, doxorubicin andepidoxorubicin; Vitamin A derivatives including retinoids andall-trans-retinoic acid (See Ellison R. R. et.al. (1968) Blood 32:507,Arabinosyl Cytosine: A useful agent in the treatment of leukemia inadults; Cytarabine: Therapeutic new dimensions, Semin. Oncol. 12:1(1985, supp 3); Weinstein H. J. et. al. (1983) Blood 62:315,Chemotherapy for acute myelogenous leukemia in children and adultsresults in an enhanced therapeutic response.

Accordingly, in a fifth alternative embodiment the invention concerns apharmaceutical composition comprising:

a pharmaceutical carrier, a therapeutically effective amount of compoundselected from the group consisting of epsilon-aminocaproic acid,heparin, trasylol, prednisolone, cytosine arabinoside, β-mercaptopurine,cytarabine, an anthracycline and a vitamin A derivative; and atherapeutically effective amount of compound of Formula I as definedabove.

In a sixth alternative embodiment the invention concerns a method oftreating leukemia comprising:

co-administration to a patient in need of such treatment of atherepeutically effective amount of compound selected from the groupconsisting of epsilon-aminocaproic acid, heparin, trasylol,prednisolone, cytosine arabinoside, b-mercaptopurine, cytarabine, ananthracycline, and a vitamin A derivative; and a therapeuticallyeffective amount of compound of Formula I as defined above.

In a seventh alternative embodiment the invention concerns a method ofinhibiting proteinase 3/myeloblastin, comprising:

co-administration to a patient in need of such inhibition of atherapeutically effective amount of compound selected from the groupconsisting of epsilon-aminocaproic acid, heparin, trasylol,prednisolone, cytosine arabinoside, β-mercaptopurine, cytarabine, ananthracycline, and a vitamin A derivative; and a therapeuticallyeffective amount of compound of Formula I as defined above.

In an eighth alternative embodiment the invention concerns a method ofinhibiting proteinase 3/myeloblastin and elastase, comprising:

administration to a patient in need of such inhibition of atherapeutically effective amount of compound selected from the groupconsisting of epsilon-aminocaproic acid, heparin, trasylol,prednisolone, cytosine arabinoside, β-mercaptopurine, cytarabine, ananthracycline, and a vitamin A derivative; and a therapeuticallyeffective amount of compound of Formula I as defined above.

In a ninth alternative embodiment the invention concerns a method ofinducing cell differentiation in leukemia cells comprising:

administration to a patient in need of such inducing of atherapeutically effective amount of compound selected from the groupconsisting of epsilon-amino-caproic acid, heparin, trasylol,prednisolone, cytosine arabinoside, β-mercaptopurine, cytarabine, ananthracycline and a vitamin A derivative; and a therapeuticallyeffective amount of compound of Formula I as defined above.

In a tenth alternative embodiment of the invention the instant compoundscan also be used in the treatment of diseases associated withover-expression of cDNa, such as those pulmonary diseases is withabnormal, viscous, or inspissated purulent secretions. Such conditionsare found in acute or chronic bronchopulmonary disease includinginfectious pneumonia, bronchitis or tracheobronchitis, bronchiectasis,cystic fibrosis, asthma, tuberculosis or fungal infections. Utility isalso found in atelactasis due to tracheal or btonchial impaction andcomplications of tracheostomy.

In addition, the instant compounds can be co-administered with cDNasewhich also finds utility in these pulmonary diseases, and which isdescribed in WO 90/07572.

The compounds of the invention are prepared by known methods or areprepared among other methods by the following representative schemes.For example, methods for making such compounds are disclosed in EP 0 337549, published Oct. 18, 1989, which is hereby incorporated by reference.

This invention also relates to a method of treating inflammation inpatients using a compound of Formula (I), particularly a preferredcompound as the active constituent.

It has been found that the following compound are effective inhibitorsof the proteolytic function of human neutrophil elastase as shown belowin Table 1 to 10.

                  TABLE 1                                                         ______________________________________                                         ##STR18##                                                                    No.   A                       Kobs/ I!                                        ______________________________________                                         1    CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                                   1,566,000                                        2    CH.sub.2 CO.sub.2 H     1,667,000                                        3    CH.sub.2 C(O)N(CH.sub.2 CH.sub.2 OH).sub.2                                                            3,428,000                                        4    CH.sub.2 C(O)N(CH.sub.3)CH.sub.2 C(O)NH.sub.2                                                         4,293,000                                        5    CH.sub.2 C(O)NHC(CH.sub.2 OH).sub.3                                                                   4,448,000                                        6    CH.sub.2 C(O)N(CH.sub.3).sub.2                                                                        2,997,000                                        7    CH.sub.2 CH.sub.2 N(CH.sub.3)Ac                                                                       1,558,000                                        8    CH.sub.2 C(O)-Pro-OCH.sub.2 Ph                                                                        12,501,000                                       9    CH.sub.2 C(O)-Pro-OH    1,571,000                                       10    CH(CH.sub.3)CO.sub.2 CH.sub.2 Ph                                                                      2,891,000                                       11    CH(CH.sub.3)CO.sub.2 H  1,132,000                                       12    CH(CH.sub.3)C(O)N(Et).sub.2                                                                           2,815,000                                       13    CH(CH.sub.3)CH.sub.2 N(CH.sub.3).sub.2                                                                2,472,000                                       14    CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                          2,855,000                                       15    CH.sub.2 CH.sub.2 N(O)(CH.sub.3).sub.2                                                                2,162,000                                       16    CH.sub.2 CH.sub.2 N(Et).sub.2                                                                         2,291,000                                       17    CH.sub.2 CH.sub.2 (4-morpholinyl)                                                                     4,733,000                                       18    CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                 1,934,000                                       19    CH.sub.2 C(O)-Pro-NHCH.sub.2 Ph                                                                       4,956,000                                       20    CH.sub.2 C(CH.sub.3).sub.2 N(CH.sub.3).sub.2                                                          1,470,000                                       21    CH.sub.2 CH.sub.2 N(i-Pr).sub.2                                                                       1,671,000                                       22    CH.sub.2 CH.sub.2 (4-carbobenzyloxy-1-piperazinyl)                                                    4,115,000                                       23    CH.sub.2 CH.sub.2 N(n-Bu).sub.2                                                                         992,000                                       24    CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).su          b.2                     1,988,000                                       25    CH.sub.2 CH.sub.2 (1-piperazinyl)                                                                     1,709,000                                       26    CH.sub.2 CH.sub.2 (4-methyl-1-piperazinyl)                                                            4,685,000                                       27    CH.sub.2 CH.sub.2 (4-acetyl-1-piperazinyl)                                                            3,262,000                                       28    CH.sub.2 CH.sub.2 N(Ph).sub.2                                                                           188,000                                       29    CH.sub.2 CH.sub.2 N(CH.sub.2 CHCH.sub.2).sub.2                                                          891,000                                       30    CH.sub.2 CH(Ph)N(CH.sub.3).sub.2                                                                        656,000                                       31    CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                              1,180,000                                       ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                         ##STR19##                                                                    No.       A                Kobs/ I!                                           ______________________________________                                        32        CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                            1,993,000                                          33        CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                   1,151,000                                          34        CH.sub.2 CH.sub.2 N(Et).sub.2                                                                  1,339,000                                          35        CH.sub.2 CH.sub.2 -(4-morpholinyl)                                                             1,725,000                                          36        CH(CH.sub.3)CH.sub.2 N(CH.sub.3).sub.2                                                         1,688,000                                          37        CH.sub.2 C(CH.sub.3).sub.2 N(CH.sub.3).sub.2                                                   2,100,000                                          38        CH.sub.2 CO.sub.2 H                                                                            1,008,000                                          39        CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                         751,000                                          ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                         ##STR20##                                                                    No.   A                        Kobs/ I!                                       ______________________________________                                        40    N(CH.sub.2 CH.sub.2 OH).sub.2                                                                          1,241,000                                      41    4-methyl-1-piperazinyl     974,000                                      42    4-morpholinyl            1,088,000                                      43    NHCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                                  1,211,000                                      44    N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                         1,243,000                                      45    NHCH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                         1,118,000                                      46    NHCH.sub.2 CH.sub.2 -(4-pyridyl)                                                                       2,254,000                                      47    NHCH.sub.2 CO.sub.2 H      876,000                                      48    NHCH(CH.sub.3)CO.sub.2 H   676,000                                      49    NHCH.sub.2 C(O)N(CH.sub.2 CH.sub.2 OH).sub.2                                                           1,295,000                                      50    N(CH.sub.3)CH.sub.2 CO.sub.2 H                                                                           989,000                                      51    NHCH(CH.sub.3)C(O)N(CH.sub.2 CH.sub.2 OH).sub.2                                                          939,000                                      52    N(CH.sub.3)CH.sub.2 C(O)N(CH.sub.2 CH.sub.2 OH).sub.2                                                    273,000                                      53    N(CH.sub.3)CH.sub.2 CH.sub.2 -(4-morpholinyl)                                                          2,511,000                                      54    N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2 OCH.sub.3).sub.2                                      1,388,000                                      55    N(CH.sub.3)CH.sub.2 CH.sub.2 N(Et).sub.2                                                               1,316,000                                      56    N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                1,047,000                                      57    NHCH.sub.2 CH(CH.sub.3)N(CH.sub.3).sub.2                                                               1,344,000                                      58    N(CH.sub.3)CH.sub.2 CH.sub.2 N(i-Pr).sub.2                                                             1,634,000                                      59    N(n-Pr).sub.2            1,144,000                                      60    N(Et).sub.2              1,079,000                                      61    3-chloroanilino-           733,000                                      62    3-methoxyanilino-        1,621,000                                      63    4-fluoroanilino-                                                        64    N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 H                                                         917,000                                      65    N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 C(O)NHSO.sub.2 Ph                                                1,335,000                                      66    N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                           1,355,000                                      67    N(CH.sub.3).sub.2          942,000                                      68    N(CH.sub.3)CH.sub.2 Ph   1,897,000                                      69    N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                    2,792,000                                      70    NHOCH.sub.2 Ph           2,371,000                                      71    N(CH.sub.3)(4-carboxyphenyl)                                                                           1,508,000                                      72    N(CH.sub.3)(4-benzenesulfonyl-amino-carbonyl-                                                          3,284,000                                            phenyl)                                                                 ______________________________________                                    

                                      TABLE 4                                     __________________________________________________________________________     ##STR21##                                                                    No. A                           Kobs/ I!                                      __________________________________________________________________________    73  NHCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                                     968,000                                       74  NHCH.sub.2 CO.sub.2 H       1,434,000                                     75  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                            1,916,000                                     76  N(Et)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                                  1,436,000                                     77  NHCH.sub.2 CH.sub.2 N(Et).sub.2                                                                           1,187,000                                     78  NHCH.sub.2 CH.sub.2 -(4-morpholinyl)                                                                      1,841,000                                     79  N(CH.sub.3)CH.sub.2 CH.sub.2 -(4-morpholinyl)                                                             2,118,000                                     80  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2 OCH.sub.3).sub.2                                         2,078,000                                     81  N(CH.sub.3)CH.sub.2 CH.sub.2 N(Et).sub.2                                                                  2,191,000                                     82  N(Ph)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                                  2,504,000                                     83  N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                   1,797,000                                     84  NHCH.sub.2 CH.sub.2 N(i-Pr).sub.2                                                                         2,100,000                                     85  N(CH.sub.3)CH.sub.2 CH.sub.2 N(O)(CH.sub.3).sub.2                                                         1,589,000                                     86  N(CH.sub.3)CH.sub.2 CH.sub.2 N(i-Pr).sub.2                                                                2,449,000                                     87  NHSO.sub.2 CH.sub.2 CH.sub.2 -(4-morpholinyl)                                                             775,000                                       88  NHSO.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                            788,000                                       89  NHCH.sub.2 CH.sub.2 -(4-imidazolyl)                                                                       2,092,000                                     90  NHCH.sub.2 CH.sub.2 -(1-piperidinyl)                                                                      941,000                                       91  N(CH.sub.3)CH.sub.2 CH.sub.2 -(1-piperidinyl)                                                             892,000                                       92  N(CH.sub.3)CH.sub.2 CH.sub.2 NHCH.sub.3                                                                   1,453,000                                     93  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)Ac                                                                1,960,000                                     94  NHCH.sub.2 CH.sub.2 -(1-pyrrolidinyl)                                                                     1,239,000                                     95  N(CH.sub.3)CH.sub.2 CH.sub.2 -(1-pyrrolidinyl)                                                            1,005,000                                     96  NHCH.sub.2 CH.sub.2 -(1H-1,2,4-triazol-1-yl)                                                              1,397,000                                     97  NHCH.sub.2 CH.sub.2 -(1-imidazolyl)                                                                       1,070,000                                     98  NHCH.sub.2 CH.sub.2 -(3-azabicyclo- 3.2.2-non-3-yl)                                                       3,043,000                                     99  NHCH.sub.2 CH.sub.2 -(3-azaspiro 5.5!-undec-3-yl)                                                         2,583,000                                     100 NHCH.sub.2 CH.sub.2 -(2H-tetrazol-2-yl)                                                                   2,006,000                                     101 NHCH.sub.2 CH.sub.2 -(1H-tetrazol-1-yl)                                                                   2,053,000                                     102 NHCH.sub.2 C(O)ProNHCH.sub.2 Ph                                                                           2,747,000                                     103 N(CH.sub.3)CH.sub.2 CH.sub.2 -(3-azabicyclo- 3.2.2!non-3-yl)                                              2,996,000                                     104 N(CH.sub.3)CH.sub.2 CH.sub.2 -(4-imidazolyl)                                                              2,389,000                                     105 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)Ac                                                                2,398,000                                     106 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)C(O)NHCH.sub.3                                                    2,486,000                                     107 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)SO.sub.2 CH.sub.3                                                 2,530,000                                     108 N(CH.sub.3)CH.sub.2 CH.sub.2 (3-azabicyclo- 3.2.2!-non-3-yl)                                              2,953,000                                     109 NHCH.sub.2 CH.sub.2 -(1,1-dioxo-4-thiamorpholinyl)                                                        1,275,000                                     110 4-dimethylaminobenzylamino  5,598,000                                     111 3-dimethylaminoanilino      2,286,000                                     112 N(CH.sub.3)CH.sub.2 CH.sub.2 -(1,1-dioxo-4-thia-morpholinyl)                                              1,596,000                                     113 4-dimethylaminoanilino      2,591,000                                     114 NHCH.sub.2 CH.sub.2 -(1-benzyl-1H-imidazol-2-yl)                                                          3,853,000                                     115 N(CH.sub.3)CH.sub.2 CH.sub.2 (2-pyridyl)                                                                  2,272,000                                     116 N(CH.sub.3)(1-azabicyclo 2.2.2!oct-3-yl                                                                   3,480,000                                     117 NHCH.sub.2 CH.sub.2 (4-benzyloxycarbonyl-1-piperazinyl)                                                   6,231,000                                     118 1,2-diethylpyrazolidin-4-ylamino                                                                          1,001,000                                     119 2-(1-S-pyrrolidinylmethyl)-1-pyrrolidinyl                                                                 2,692,000                                     120 NHCH.sub.2 CH.sub.2 (4-hydroxy-1-piperidinyl)                                                             1,728,000                                     121 NHCH.sub.2 CH.sub.2 (1-homopiperidinyl)                                                                   2,069,000                                     122 N(CH.sub.3)CH.sub.2 CH.sub.2 (1-homopiperidinyl)                                                          2,899,000                                     123 NHCH.sub.2 CH.sub.2 (3-hydroxy-1-piperidinyl)                                                             1,534,000                                     124 N(CH.sub.3)CH.sub.2 CH.sub.2 (3-hydroxy-1-piperidinyl)                                                    1,963,000                                     125 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                       2,054,000                                     126 N(CH.sub.3)CH.sub.2 CH.sub.2 (4-benzyloxy-1-piperidinyl)                                                  3,476,000                                     127 N(n-Pr).sub.2               990,000                                       128 N(Et).sub.2                 1,454,000                                     129 N(CH.sub.3)CH.sub.2 CH.sub.2 (4-hydroxy-1-piperidinyl)                                                    1,994,000                                     130 N(CH.sub.3)CH.sub.2 CH.sub.2 (4-oxo-1-piperidinyl)                                                        2,297,000                                     131 NHCH.sub.2 CH.sub.2 (3-hydroxy-1-pyrrolidinyl)                                                            1,111,000                                     132 N(Et)CH.sub.2 CH.sub.2 (1-piperidinyl)                                                                    1,244,000                                     133 N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 (1-piperidinyl)                                                           1,521,000                                     134 4-fluoroanilino-            724,000                                       135 3-chloroanilino-            201,000                                       136 3-methoxyanilino                                                          137 N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                         1,380,000                                     138 N(CH.sub.3)CH.sub.2 CH.sub.2 (3-hydroxy-1-pyrrolidinyl)                                                   960,000                                       139 N(3-picolyl)CH.sub.2 CH.sub.2 (1-piperidinyl)                                                             1,189,000                                     140 NHCH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 N(Et).sub.2                                                      1,361,000                                     141 NHCH.sub.2 CH.sub.2 (2-S-hydroxymethyl-1-pyrrolidinyl                                                     1,507,000                                     142 N(CH.sub.3)CH.sub.2 CH.sub.2 (4-t-butoxycarbonyl-1-piperazinyl)                                           3,471,000                                     143 N CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 !.sub.2                                                             1,878,000                                     144 N CH.sub.2 CH.sub.2 N(Et).sub.2 !.sub.2                                                                   1,508,000                                     145 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(3-picolyl)                                                       2,877,000                                     146 3,5-dimethyl-1-piperazinyl  1,518,000                                     147 N(CH.sub.3)CH.sub.2 CH.sub.2 N(O)(CH.sub.3)CH.sub.2 Ph                                                    2,493,000                                     148 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-picolyl)                                                       2,389,000                                     149 2-S-(N-benzyl-N-methylaminomethyl)-1-pyrrolidinyl                                                         3,268,000                                     150 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2-picolyl)                                                       2,165,000                                     151 N(CH.sub.3)CH.sub.2 CH.sub.2 (1-piperazinyl)                                                              1,191,000                                     152 1-homopiperazinyl           1,951,000                                     153 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 CH.sub.2 Ph                                              2,797,000                                     154 2-(1-R-pyrrolidinylmethyl)-1-pyrrolidinyl                                                                 1,666,000                                     155 4-benzyl-1-homopiperazinyl  1,979,000                                     156 N(CH.sub.3)CH.sub.2 CH(OH)!.sub.4 CH.sub.2 OH                                                             1,198,000                                     157 N(CH.sub.3)CH.sub.2 CH(OAc)!.sub.4 CH.sub.2 OAc                                                           1,171,000                                     158 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(1-Naphthalenylmethyl)                                            1,075,000                                     159 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2-Naphthalenylmethyl)                                            1,337,000                                     160 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH(CH.sub.3)Ph                                                    1,569,000                                     161 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.2 Ph).sub.2                                                         1,021,000                                     162 1-ethyl-3-piperidinylamino  949,000                                       163 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2-furfuryl)                                                      1,818,000                                     164 N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 H                                                          1,064,000                                     165 N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 C(O)NHSO.sub.2 Ph                                                   1,550,000                                     166 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 CHCH.sub.2                                               1,359,000                                     167 N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                              1,293,000                                     168 N(CH.sub.3)(CH.sub.2).sub.6N(CH.sub.3)CH.sub.2 Ph                                                         2,157,000                                     169 N(CH.sub.3)CH.sub.2 CH.sub.2 OH                                                                           1,457,000                                     170 N(CH.sub.3)CH.sub.2 CH.sub.2 OC(O)N(CH.sub.3).sub.2                                                       1,518,000                                     171 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 CO.sub.2 -t-Bu                                           1,831,000                                     172 N(CH.sub.3)(1-ethyl-3-piperidinyl)                                                                        1,545,000                                     173 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(tetrahydro-2H-pyran-2-yl-meth        yl)                         2,943,000                                     174 2,2,6,6-tetramethylpiperidin-4-ylamino                                                                    869,000                                       175 N(CH.sub.3)(4-carboxyphenyl)                                                                              1,055,000                                     176 N(CH.sub.3)(4-benzenesulfonylaminocarbonyl-phenyl                                                         3,231,000                                     177 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-cyanobenzyl)                                                   2,201,000                                     178 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-methylbenzyl)                                                  1,870,000                                     179 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(3-cyanobenzyl)                                                   2,448,000                                     180 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-trifluoro-methylbenzyl                                         905,000                                       181 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(3-trifluoromethyl-benzyl)                                        564,000                                       182 N(CH.sub.3)CH.sub.2 CH.sub.2 (CH.sub.3)(4-fluorobenzyl)                                                   2,137,000                                     183 NHCH(CH.sub.3)PH(O)OH       977,000                                       184 L-lysine (α-N)        755,000                                       185 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(cyclopropylmethyl)                                               1,787,000                                     186 N(CH.sub.3)CH.sub.2 CH(Ph)N(CH.sub.3).sub.2                                                               1,053,000                                     187 N(CH.sub.3).sub.2           1,749,000                                     188 N(CH.sub.3)CH.sub.2 Ph      1,837,000                                     189 N(CH.sub.3)(1-benzyl-3-piperidinyl)                                                                       1,879,000                                     190 NHOCH.sub.2 Ph              1,797,000                                     191 N(3-picolyl)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 PH                                                      2,538,000                                     192 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-methoxybenzyl)                                                 1,785,000                                     193 N(4-picolyl)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                      2,243,000                                     194 N(2-picolyl)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                      2,473,000                                     195 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2,4-dimethylbenzyl)                                              1,119,000                                     196 N(CH.sub.3)CH.sub.2 CH.sub.2 (2,6-dimethyl-4-morpholinyl)                                                 1,530,000                                     197 NH.sub.2                    1,638,000                                     198 NHCH.sub.3                  1,825,000                                     199 4-morpholinyl               2,376,000                                     200 cis-2,6-dimethyl-4-morpholinyl                                                                            1,837,000                                     201 NHCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                                     2,460,000                                     202 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)C(NCN)NHPh                                                        1,763,000                                     203 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(3-fluorobenzyl)                                                  1,262,000                                     204 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2-chlorobenzyl)                                                  1,591,000                                     205 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(3-methoxybenzyl)                                                 1,911,000                                     206 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(3,5-dimethoxybenzyl)                                             1,735,000                                     207 3,4-dihydro-6,7-dimethoxy-2-(1H)iso-quinolinyl                                                            2,698,000                                     208 N(CH.sub.3)(1-benzyl-4-piperidinyl)                                                                       1,948,000                                     209 L-lysine (ε-N)      929,000                                       210 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2-adamantyl)                                                     2,132,000                                     211 N(CH.sub.3)(4-piperidinyl)  85,000                                        212 5-Methyl-2,5-diazabicyclo 2.2.1!hept-2-yl                                                                 860,000                                       213 N(CH.sub.3)CH.sub.2 CO.sub.2 H                                                                            984,000                                       214 N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 CH.sub.3                                        1,099,000                                     215 N(CH.sub.3)(1-methyl-4-piperidinyl)                                                                       1,283,000                                     216 N(CH.sub.3)(1-propyl-4-piperidinyl)                                                                       1,312,000                                     217 N(CH.sub.3)(1-ethyl-4-piperidinyl)                                                                        1,422,000                                     218 N(CH.sub.3)CH.sub.2 CH(CH.sub.3)N(CH.sub.3)CH.sub.2 Ph                                                    2,123,000                                     219 N(CH.sub.3)CH.sub.2 CH(CH.sub.3)N(CH.sub.3).sub.2                                                         1,588,000                                     220 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(bicyclo 2.2.1!-hept-2-yl)                                        1,874,000                                     221 N(CH.sub.3)CH.sub.2 CH.sub.2 NH(2-adamantyl)                                                              3,010,000                                     222 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(6,6-dimethylbicyclo- 3.1.1!he        pt-2-yl                     2,288,000                                     223 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(bicyclo 3.2.1!-oct-2-yl)                                         2,584,000                                     224 NH(t-Bu)                                                                  225 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(1-cyclohexen-1-yl)                                               1,839,000                                     226 N(CH.sub.3)CH.sub.2 CH.sub.2 NHC(CH.sub.3).sub.2 CHCH.sub.2                                               1,309,000                                     227 2-S-carboxamido-1-pyrrolidinyl                                                                            931,000                                       228 2-hydroxymethyl-1-piperidinyl                                                                             50,000                                        229 3-dimethylamino-1-pyrrolidinyl                                                                            1,336,000                                     230 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(cyclohexylmethyl)                231 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.2 CHCH.sub.2)C(CH.sub.3).sub.2          CHCH.sub.2                  925,000                                       232 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-ethylcyclohexyl)                                               2,476,000                                     233 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2-ethylcyclohexyl)                                               2,030,000                                     234 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-methylcyclohexyl)                                              2,166,000                                     235 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(cyclohexyl)                                                      1,952,000                                     236 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 CO.sub.2 H TFA                                           31,000                                        237 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 C(O)N(CH.sub.3).sub.2        1                           2,679,000                                     238 3-dimethylamino-1-azetidinyl                                              239 1-diphenylmethyl-3-azetidinyl                                             240 N(CH)CH.sub.2 CH.sub.2 N(CH.sub.3)(cyclohexylmethyl)                                                      3,003,000                                     241 NHCH.sub.2 CH.sub.2 N(Et)CH.sub.2 CH.sub.2 OCH.sub.3                                                      1,090,000                                     __________________________________________________________________________

                  TABLE 5                                                         ______________________________________                                         ##STR22##                                                                    No.        R               Kobs/ I!                                           ______________________________________                                        242        CH3             1,700,000                                          243        4-fluorophenyl  7,486,000                                          244        3-chlorophenyl  2,453,000                                          245        phenyl          5,276,000                                          246        benzyl          5,171,000                                          247        H               1,100,000                                          248        i-Pr            2,392,000                                          249        i-Bu            2,476,000                                          250        CH.sub.2 CO.sub.2 Et                                                                          1,571,000                                          251        CH.sub.2 CO.sub.2 H                                                                           1,947,000                                          252        Et              2,324,000                                          253        Pr              1,768,000                                          254        2-pyrimidinyl   2,142,000                                          255        CH.sub.2 CH.sub.2 OC(O)NHCH.sub.3                                                             2,548,000                                          256        cyclopropyl     3,587,000                                          256a       CH.sub.2 CH.sub.2 OH                                                                          2,000,000                                          ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                         ##STR23##                                                                    No.    n       A                  Kobs/ I!                                    ______________________________________                                        257    1       NH.sub.2           2,342,000                                   258    1       4-morpholinyl      1,785,000                                   259    1       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                   2,522,000                                   260    0       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                   3,317,000                                   261    0       N(Et).sub.2        3,207,000                                   262    0       N(CH.sub.3)(n-Bu)  3,125,000                                   263    0       4-methyl-1-piperazinyl                                                                           3,805,000                                   264    0       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                              3,427,000                                   265    0       4-cyclopropyl-1-piperazinyl                                                                      4,500,000                                   265a   0       1-piperazinyl      3,250,000                                   265c   0       4-(2-hydroxyethyl)-1-piperazinyl                                                                 4,800,000                                   265d   0       4-morpholinyl      3,700,000                                   ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                         ##STR24##                                                                    No.  n       R.sub.4 A              Kobs/ I!                                  ______________________________________                                        266  1       H       4-morpholinyl  169,000                                   267  1       H       N(Et).sub.2    334,000                                   268  1       H       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                               142,000                                   269  1       CH.sub.3                                                                              NH.sub.2       637,000                                   270  1       CH.sub.3                                                                              N(Et).sub.2    740,000                                   271  1       CH.sub.3                                                                              N(n-Pr).sub.2  826,000                                   272  0       Et      N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                               2,423,000                                 273  0       Et      N(CH.sub.3)(n-Bu)                                                                            3,258,000                                 ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                         ##STR25##                                                                    No.     n     R.sub.3 A              Kobs/ I!                                 ______________________________________                                        274     1     H       NH.sub.2       430,000                                  275     1     H       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                               290,000                                  276     1     H       OCH.sub.3      440,000                                  277     0     H       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                               548,000                                  278     0     H       OCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                         135,000                                  279     0     H       N(Et).sub.2    566,000                                  280     0     H       4-morpholinyl  577,000                                  ______________________________________                                    

                                      TABLE 9                                     __________________________________________________________________________     ##STR26##                                                                    No.                                                                              n R.sub.3  R.sub.2       A              Kobs/ I!                           __________________________________________________________________________    281                                                                              1 H        CO.sub.2 H    4-morpholinyl   62,000                            282                                                                              1 H        CO.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                4-morpholinyl  421,000                            283                                                                              1 H        CON(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                            4-morpholinyl  393,000                            284                                                                              1 H        OH            N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                N              309,000                            285                                                                              1 H        OCH.sub.3     N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                O              566,000                            286                                                                              0 H        CON(CH.sub.3).sub.2                                                                         N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                N              551,000                            287                                                                              0 H        CO.sub.2 H    N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                O              113,000                            288                                                                              0 H        CH.sub.2 OH   N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                N              854,000                            289                                                                              1 H        OCH.sub.3     N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                O              754,000                            290                                                                              0 H        OCH.sub.3     N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                A              1,010,000                          291                                                                              0 OCH.sub.3                                                                              H             N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                B              1,754,000                          292                                                                              1 CH.sub.2 OCON(Et).sub.2                                                                CH.sub.3      4-morpholinyl  807,000                            293                                                                              1 CON(n-Pr).sub.2                                                                        CH.sub.3      N(Et).sub.2    457,000                            294                                                                              1 CON(n-Pr).sub.2                                                                        CH.sub.3      4-morpholinyl  255,000                            295                                                                              0 H        CN            N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                S              846,000                            296                                                                              0 H        OEt           N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub                                .2 Ph          776,000                            297                                                                              0 H        2-(4-morpholinocarbonylphenyl)                                                              N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub                                .2 Ph          1,077,000                          298                                                                              0 H        OCH.sub.3     4-methyl-1-piperazinyl                                                                       1,845,000                          299                                                                              0 H        Cl            N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                1              1,475,000                          300                                                                              0 H        Cl            N(CH.sub.3)CH.sub.2 CH.sub.2 N(Et).sub.2                                                     1,282,000                          301                                                                              0 H        Cl            N(CH.sub.3)CH.sub.2 CH.sub.2 N(i-Pr).sub.2                                                   1,497,000                          302                                                                              0 H        Cl            N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub                                .2 Ph          1,462,000                          303                                                                              0 OCH.sub.3                                                                              CH.sub.3      N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2    __________________________________________________________________________

                  TABLE 10                                                        ______________________________________                                         ##STR27##                                                                    No.   R.sub.2 R.sub.6 A               Kobs/ I!                                ______________________________________                                        304   CH.sub.3                                                                              CH.sub.3                                                                              OCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                          563,000                                 305   CH.sub.3                                                                              CH.sub.3                                                                              OCH.sub.2 CH.sub.2 N(Et).sub.2                                                                749,000                                 306   CH.sub.3                                                                              CH.sub.3                                                                              OCH.sub.2 CH.sub.2 N(i-Pr).sub.2                                                              612,000                                 307   CH.sub.3                                                                              CH.sub.3                                                                              N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                352,000                                 308   CH.sub.3                                                                              CH.sub.3                                                                              N(CH.sub.3)CH.sub.2 CH.sub.2 N(Et).sub.2                                                      377,000                                 309   CH.sub.3                                                                              CH.sub.3                                                                              N(Et)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                      398,000                                 310   H       OH      N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                838,000                                 ______________________________________                                    

Enzyme Assays for the Inhibition of Human Polymorphonuclear LeukocyteElastase Via Hydrolysis ofN-t-Boc-alanyl-alanyl-prolylalanine-p-nitroanilide (Boc-AAPAN) orN-t-Boc-alanyl-prolylvaline-p-nitroanilide (Boc-AAPVN) Reagent:

0.05M TES (N-tris hydroxymethyl!methyl-2-mino-ethanesulfonic acid)Buffer, pH 7.5.

0.2 mM Boc-AAPAN or Boc-AAPVN.

To prepare substrate, the solid was first dissolved in 10.0 ml DMSO.Buffer at pH 7.5 was then added to a final volume of 100 ml.

Crude extract of human polymorphonuclear leukocytes (PMN) containingelastase activity.

Inhibitors (azetidinones) to be tested dissolved in DMSO just beforeuse.

To 1.0 ml of 0.2 mM Boc-AAPAN in a cuvette, 0.01-0.1 ml of DMSO with orwithout inhibitor was added. After mixing, a measurement was taken at410 mμ to detect any spontaneous hydrolysis due to presence of testcompound. 0.05 Milliliters of PMN extract was then added and the ΔOD/minat 410 mμ was measured and recorded. Beckman model 35 spectrophotometerwas used.

Results were expressed to the nearest thousand ^(k) obs/I which is thesecond order rate constant in per mole per second for inactivation ofthe enzyme.

The elastase activity in the crude PMN extract may vary from onepreparation to another. A control of each new batch is run, and thevolume added in the assay procedure is adjusted according to activity.

This invention also relates to a method of treating inflammation inpatients using a compound of Formula (I), particularly a preferredcompound as the active constituent.

It has been found that the compounds of Formula (I) are effectiveinhibitors of the proteolytic function of human neutrophil elastase.

Accordingly, the compounds of Formula (I), can be used to reduceinflammation and/or relieve pain in diseases such as emphysema,rheumatoid arthritis, osteoarthritis, gout, bronchial inflammation,chronic or acute bronchitis, cystic fibrosis, adult respiratory distresssyndrome, atherosclerosis, sepsis, septicemia, shock, periodontitis,glomerular nephritis or nephosis, myocardial infarction, reperfusioninjury, infectious arthritis, rheumatic fever and the like, and mayreduce hemorrhage in acute promyelocytic leukemia and the like.

In this capacity, and as appreciated by those of skill in the art,therapy comprising administration of compounds of Formula I may actuallyinclude co-administration of one or more additional active agents.Classes of active agents include, but are not limited to β₂ -adrenergicagonists; anti-cholinergic agents; steroids; non-steroidalanti-inflammatory agents (NSAID's); mucolytic agents; most allstabilizers; and antibacterials.

For purposes of this specification, β₂ -adrenergic agonists are intendedto include, but are not limited to, metaproterenol, terbutaline,isoetharine, albuterol, and ritodrine, carbuterol, fenoterol,quinterenol, rimiterol, salmefamol, soterenol, and tretoquinol.

For purposes of this specification, anti-cholinergic agents are intendedto include, but are not limited to, atropine, and iptratropium-bromide.

For purposes of this specification, mucolytic agents are intened toinclude, but are not limited to acetylcysteine and guattenesin.

For purposes of this specification, steroids are intended to include,but are not limited to, prednisone, beclomethasone, budesonide,solumedrol, triamcinolone, and methyl-prednisolone.

For purposes of this specification most cell stabilizers are intended toinclude, but are not limited to cromolyn and ketotafin.

For purposes of this specification, non-steroidal anti-inflammatoryagents are intended to include, but are not limited to aspirin,diflunisal, naphthylsalicylate, phenylbutazolone, oxyphenbutazolone,indomethacin, sulindac, mefenamic acid, meclofenamate sodium, tolmetin,ibuprofen, naproxen, fenoprofen and piroxicam.

For the purposes of this specification, antibacterial agents areintended to include the broad classes of penicillins, cephalosporins andother beta-lactams, aminoglycosides, quinolones, macrolides,tetracyclines, sulfonamides, lincosamides and polymyxins. Thepenicillins, in turn, are intended to include, but are not limited topenicillin G, penicillin V, methicillin, nafcillin, oxacillin,cloxacillin, dicloxacillin, floxacillin, ampicillin,ampicillin/sulbactam, amoxicillin, amoxicillin/clavulanate, hetacillin,cyclacillin, bacampicillin, carbenicillin, carbenicillin indanyl,ticarcillin, ticarcillin/clavulanate, azlocillin, mezlocillin,peperacillin, and mecillinam. The cephalosporins and other beta-lactamsare intended to include, but are not limited to cephalothin, cephapirin,cephalexin, cephradine, cefazolin, cefadroxil, cefaclor, cefamandole,cefotetan, cefoxitin, ceruroxime, cefonicid, ceforadine, cefixime,cefotaxime, moxalactam, ceftizoxime, cetriaxome, ceftizoxime,cetriaxone, cephoperazone, ceftazidime, imipenem and aztreonam. Theaminoglycosides are intended to include, but are not limited tostreptomycin, gentamicin, tobramycin, amikacin, netilmicin, kanamycinand neomycin. The quinolones are intended to include, but are notlimited to nalidixic acid, norfloxacin, enoxacin, ciprofloxacin,ofloxacin, sparfloxacin and temafloxacin. The macrolides are intended toinclude, but are not limited to erythomycin, spiramycin andazithromycin. The tetracyclines are intended to include, but are notlimited to doxycycline, minocycline and tetracycline. The sulfonamidesare intended to include, but are not limited to sulfanilamide,sulfamethoxazole, sulfacetamide, sulfadiazine, sulfisoxazole andco-trimoxazole (trimethoprim/sulfamethoxazole). The lincosamides areintended to include, but are not limited to clindamycin and lincomycin.The polymyxins (polypeptides) are intended to include, but are notlimited to polymyxin B and colistin.

Alternatively, compounds of Formula I are useful in the treatment ofcertain cancers including nonlymphoblastic leukemias, acute myelogenousleukemia (FAB M1 and FAB M2), acute promyelocytic leukemia (FAB M3),acute myelomonocytic leukemia (FAB M4), acute monocyte leukemia (FABM5), erythroleukemia, chronic myelogenous leukemia, chronicmyelomonocytic leukemia, chronic monocytic leukemia and conditionsassociated with leukemia involving activity of PMN neutral proteasese.g. disseminated intravascular coagulation.

Similarly, compounds of Formula I are useful for the inhibition ofproteinase 3/myeloblastin, inhibition of elastase, inhibition ofproliferation of leukemia cells, inducing differentiation of leukemiacells and remission of the disease state of leukemia.

Moreover, as described above, such treatment may optionally comprise theco-administration of an agent such as a compound selected from the groupconsisting of epsilon-aminocaproic acid, heparin, trasylol,prednisolone, cytosine arabinoside, b-mercaptopurine, cytarabine, ananthracycline and a vitamin A derivative such as retinoic acid.

For each of the uses, the compounds of Formula (I) and optionaltreatment agents, may be administered orally, topically, parenterally,by inhalation spray or rectally in dosage unit Formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. In addition to the treatment of warm-bloodedanimals such as mice, rats, horses, dogs, cats, etc., the compounds ofthe invention are effective in the treatment of humans.

For treatment as described above the compounds of Formula (I) may beadministered orally, topically, parenterally, by inhalation spray orrectally in dosage unit Formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques. Inaddition to the treatment of warm-blooded animals such as mice, rats,horses, dogs, cats, etc., the compounds of the invention are effectivein the treatment of humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparation. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.The said aqueous suspensions may also contain one or more preservatives,for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspension may be formulated by suspending the active ingredient ina vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of anantioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives.

Suitable dispersing or wetting agents and suspending agents areexemplified by those already mentioned above. Additional excipients, forexample sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oils, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan mono-oleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution glucose in water and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of Formula (I) may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the anti-inflammatory agents are employed.

The amount of active ingredient(s) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

For example, a formulation intended for the oral administration ofhumans may contain from 5 mg to 2000 mg or 5000 mg of each activeagent(s) compounded with an appropriate and convenient amount of carriermaterial which may vary from about 5 to about 95 percent of the totalcomposition. For purposes of this specification, this broad dosage rangeis specifically intended to include, but is not limited to, range of 5mg to 2000 mg; 25 mg to 2000 mg; 5 mg to 1000 mg; 25 mg to 1000 mg; 5 mgto 500 mg; and 25 mg to 500 mg. Dosage unit forms will generally containbetween from about 25 mg to about 500 mg of active ingredient(s).

Furthermore, it is also possible that most effective treatment maywarrent administration of an initial dosage of one range (e.g. 1-5 mg ofactive agent per kg of patient weight) followed by administration of asecond range (e.g. 0.1 to 1 mg of active agent per kg of pateintweight).

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

The following example illustrates the preparation of the compoundsuseful in the method of treatment of the present invention, but does notlimit the scope of the invention. Starting materials may be optionallyprepared as disclosed in EPO 337 549 published Oct. 18, 1989 which ishereby incorporated by reference. Where appropriate, compounds may beproduced and used in the form of pharmaceutically acceptable salts. Forexample, the basic coumpounds may be used in the form of a hydrochlorideor mesylate or other acceptable salt.

See Preformulation in Remington's Pharmaceutical Sciences, MackPublishing, Easton Pa. ##STR28##

The glycolic acid derivatives described herein can be prepared accordingto the following scheme. The starting acid (as carboxylate anion) may bealkylated (Ex 1A) with a suitably protected α-halo acetic acidderivative to give the glycolate ester 4 which can be deprotected (Ex1B) to the glycolic acid ester 5. Treatment of 5 with an amine utilizinga condensing agent such as dicyclohexylcarbodiimide orcarbomyldiinidazole (Ex 2) affords the deserved amide 6. Alternately,the starting acid 1 may be converted to its acid chloride 2 (Ex 3A) andtreated with a suitably protected α-hydroxyalkanoic acid (Ex 3B) in thepresence of base to give the protected ester 7. Deprotection (Ex 4),followed by conversion to the acid chloride and treatment with theappropriate amine (Ex 5) affords the desired amide 9.

EXAMPLE 1 A. t-Butoxycarbonylmethyl S-(R*,S*)!4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)-carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate.

To a solution of 0.806 gm of S-(R*,S*)!4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)-carbonyl)-4-oxo-2-azetidinyl)oxy)benzoicacid in ˜3 ml DMF is added 0.23 gm. triethylamine followed by 0.50 gm oft-butyl bromoacetate and the mixture stirred overnight at roomtemperature. Ethyl acetate (25 ml) is then added and the resultantmixture is washed with 2-10 ml water, 10 ml saturated sodiumbicarbonate, and 20 ml brine. The organic layer is dried through sodiumsulfate and concentrated in vacuo. Chromatography on Silica gel 60 (350ml column) and elution with 10% ethyl acetate in hexanes gave 0.67 gm ofthe t-Butoxycarbonylmethyl S-(R*,S*)!4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate.

In a similar manner can be prepared 2-(dimethylamino)-2-oxoethyl,(S-(R*,S*))-4-((3,3-Diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)-benzoate (Compound 6), and2-(N-methylacetamido)ethyl.{2-(R*,S*)}-4-{{3,3-Diethyl-1-{{{1-(4-methyl-phenyl)butyl}amino}carbonyl}-4-oxo-2-azetidinyl}oxy}-benzoate,(Compound 7).

B. CarboxymethylS-(R*,S*)!4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate

To the above ester is added 2 ml of anisole and the resulting mixture iscooled in an ice bath and 5 ml of ice cold trifluoroacetic acid isadded. The reaction mixture is stirred cold for three hours then allowedto come to room temperature. After 30 minutes, the reaction mixture isconcentrated in vacuo and the residue chromatographed on silica gel 60.Elution with 20% ethyl acetate in hexanes containing 1% acetic acidgives 0.53 gm of desired carboxymethylS-(R*,S*)!4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate.

Compound 2

    ______________________________________                                        Analysis:   C.sub.28 H.sub.34 N.sub.2 O.sub.7 +0.3H.sub.2 O                   Calc:       C, 65.19;   H, 6.75;  N, 5.43                                     Found:      C, 65.30;   H, 6.76;  N, 5.23                                     ______________________________________                                    

Compound 6

    ______________________________________                                        Analysis:   C.sub.30 H.sub.39 N.sub.3 O.sub.6 +0.5H.sub.2 O                   Calc:       C, 65.91;   H, 7.38;  N, 7.60                                     Found:      C, 65.71;   H, 7.63;  N, 7.50.                                    ______________________________________                                    

Compound 7

    ______________________________________                                        Analysis:   C.sub.31 H.sub.41 N.sub.3 O.sub.6 +0.6EtOAc                       Calc:       C, 66.35;   H, 7.64;  N, 6.95                                     Found:      C, 66.52;   H, 7.89;  N, 6.83.                                    ______________________________________                                    

EXAMPLE 22-(bis(2-hydroxyethyl)amino)-2-oxoethyl(S-(R*,S*))-4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)-carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate.

To a solution of 0.125 gm of the acid from 1B in 2-3 ml of methylenechloride is added 0.050 gm of carbonyldiimidazole. The mixture isstirred for 30 minutes at room temperature at which time 0.060 gm ofdiethanolamine is added along with 1 ml of DMF and 2 ml of methylenechloride. The resulting mixture is stirred overnight at room temperaturethen concentrated in vacuo. Silica gel chromatography of the residueusing 2.5 to 5.0% methanol in methylene chloride gives 0.123 gm of thedesired Compound 3,2-(bis(2-hydroxyethyl)amino)-2-oxoethyl(S-(R*,S*))-4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)-carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate.

Compound 3

    ______________________________________                                        Analysis:   C.sub.32 H.sub.43 N.sub.3 O.sub.8, +0.4H.sub.2 O                  Calc:       C, 63.53;   H, 7.30;  N, 6.95                                     Found:      C, 63,51;   H, 7.45;  N, 6.95.                                    ______________________________________                                    

Similarly were prepared

Compound 4

    ______________________________________                                        Analysis:   C.sub.31 H.sub.40 N.sub.4 O.sub.7                                 Calc:       C, 64.12;   H, 6.94;  N, 9.65                                     Found:      C, 64.12;   H, 7.18;  N, 9.44                                     ______________________________________                                    

Compound 5

    ______________________________________                                        Analysis:   C.sub.32 H.sub.43 N.sub.3 O.sub.9 +0.3H.sub.2 O                   Calc:       C, 62.08;   H, 7.09;  N, 6.79                                     Found:      C, 61.89;   H, 7.39;  N, 6.88.                                    ______________________________________                                    

Compound 8

    ______________________________________                                        Analysis:   C.sub.40 H.sub.47 N.sub.3 O.sub.8                                 Calc:       C, 68.85;   H, 6.79;  N, 6.02                                     Found:      C, 68.79;   H, 7.06,  N, 5.88.                                    ______________________________________                                    

EXAMPLE 3--PREPARATION OF1-Methyl-2-oxo-2-(phenylmethoxy)ethyl(2S-(1(S*),R*,-(R)))-4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)-amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate, Compound 10.

A.

To a solution of 1.0 gm S-(R*,S*)!4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoicacid in 10 ml methylene chloride is added 2 ml of oxalyl chloridefollowed by a catalytic amount of DMF. The reaction is stirred 1 hour atroom temperature then concentrated in vacuo to yield the acid chloridewhich is used as is in the next step.

B.

A solution of the above acid chloride in 10 ml of methylene chloride iscooled in an ice bath and a solution of 1.25 gm benzyl L-lactate and 2.0gm of triethylamine in 10 ml of methylene chloride is added. The mixtureis stirred at room temperature overnight then concentrated in vacuo.Chromatography of the residue on silica gel using methylene chloride asthe eluent yields 0.795 of the desired1-Methyl-2-oxo-2-(phenylmethoxy)ethyl (2S-(1(S*),R*,(R)))-4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate, Compound 10.

    ______________________________________                                        Analysis:   C.sub.36 H.sub.42 N.sub.2 O.sub.7                                 Calc:       C, 70.34;   H, 6.89;  N, 4.56.                                    Found:      C, 70.45;   H, 7.05;  N, 4.48.                                    ______________________________________                                    

EXAMPLE 4 PREPARATION OF 1-carboxyethylS-(R*,S*)!4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate

A mixture of 0.69 gm of the benzylester prepared in Example 3 and 0.2 gm10% Pd/C in 10 ml of EtOAc is treated with hydrogen at 40 psi. When thereaction is complete the mixture is filtered and concentrated in vacuoto yield 0.56 gm of 1-carboxy-ethylS-(R*,S*)!4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate,Compound 11.

    ______________________________________                                        Analysis:   C.sub.29 H.sub.36 N.sub.2 O.sub.7                                 Calc:       C, 66.40;   H, 6.92;  N, 5.34.                                    Found:      C, 66.66;   H, 7.26;  N, 5.05.                                    ______________________________________                                    

EXAMPLE 5 2-(diethylamino)-1-methyl-2-ozoethylS-(R*,S*)!-4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)-carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate

The acid (0.250 gm) from Example 4 is treated with oxalyl chlorideaccording to the procedure of Example 3A and the corresponding acidchloride is obtained. This material is dissolved in 5 ml methylenechloride and 0.4 ml of diethylamine added. After 1 hour the reactionmixture is concentrated in vacuo and the residue taken in ethyl acetateand washed with saturated sodium bicarbonate solution. The organic layeris dried through sodium sulfate, concentrated and the residuechromatographed on silica gel. Elution with 5% of ethyl acetate inmethylene chloride gives Compound 12.

    ______________________________________                                        Analysis:   C.sub.33 H.sub.45 N.sub.3 O.sub.6                                 Calc:       C, 68.37;   H, 7.82,  N, 7.25                                     Found:      C, 68.40;   H, 7.93,  N, 7.40.                                    ______________________________________                                    

EXAMPLE 6(S(R*,S*))-1-(((4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoyl)oxy)acetyl)L-proline,

A.

When benzyl L-lactate is replaced by L-proline benzyl esterhydrochloride and triethylamine in the procedure of Example 3 thecorresponding amide with L-proline benzyl ester, Compound 8, isobtained.

    ______________________________________                                        Analysis:   C.sub.40 H.sub.47 N.sub.3 O.sub.8                                 Calc:       C, 68.85;   H, 6.79,  N, 6.02                                     Found:      C, 68.79;   H, 7.06,  N, 5.88.                                    ______________________________________                                    

B.

Reduction of the material obtained in Example 6A according to theprocedure of Example 4 affords Compound 9.

    ______________________________________                                        Analysis:   C.sub.33 H.sub.41 N.sub.3 O.sub.8 +0.5H.sub.2 O                   Calc:       C, 64.27;   H, 6.86;  N, 6.81.                                    Found:      C, 64.49;   H, 6.90;  N, 6.68.                                    ______________________________________                                    

EXAMPLE 7S-(R*,S*)!1-(((4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl-4-oxo-2-azetidinyl)oxy)benzoyl)oxy)acetyl-N-benzyl-L-prolinamide.

Treatment of the acid obtained in Example 6B, Compound 9, with oxalylchloride according to Example 3A gives the corresponding acid chloridewhich when treated with benzylamine gives the desired benzyl amide,Compound 19.

    ______________________________________                                        Analysis:   C.sub.40 H.sub.48 N.sub.4 O.sub.7                                 Calc:       C, 68.95;   H, 6.94;  N, 8.04.                                    Found:      C, 68.93,   H, 7.02;  N, 7.96.                                    ______________________________________                                    

EXAMPLE 8

To a solution of the acid chloride (prepared from 0.55 gm ofS-(R*,S*)!4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoicacid according to the procedure of Example 3A) in 3 ml of methylenechloride is added 0.15 gm of N,N-dimethylaminoethanol. The reactionmixture is stirred overnight at room temperature, concentrated in vacuo,then taken up in ethyl acetate (25 ml) and washed with saturated sodiumbicarbonate solution. The organic layer is dried through sodium sulfateand concentrated in vacuo. Silica gel chromatography of the residueusing 2.5% methanol in methylene chloride gives 0.59 gm of Compound 1,2-(dimethylamino)ethyl(S-(R*,S*))-4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate

    ______________________________________                                        Analysis:   C.sub.30 H.sub.41 N.sub.3 O.sub.5                                 Calc:       C, 68.81;   H, 7.89;  N, 8.02.                                    Found:      C, 68.85;   H, 8.09;  N, 7.97.                                    ______________________________________                                    

When N,N-dimethylaminoethanolamine is replaced by the appropriate aminoalcohols the correponding esters are obtained.

Compound 13

1-Dimethylamino-2-propyl S-(R*,S*)!-4- 3,3-diethyl-1-1-(4-methyl-phenyl)butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoate

    ______________________________________                                        Analysis:   C.sub.31 H.sub.43 N.sub.3 O.sub.5                                 Calc:       C, 69.25;   H, 8.06;  N, 7.82.                                    Found:      C, 68.97;   H, 8.01;  N, 7.80.                                    ______________________________________                                    

Compound 14

3-Dimethylamino-1-propyl S-(R*,S*)!-4- 3,3-diethyl-1-1-(4-methyl-phenyl)butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoate

    ______________________________________                                        Analysis:   C.sub.31 H.sub.43 N.sub.3 O.sub.5                                 Calc:       C, 69.25;   H, 8.06;  N, 7.81.                                    Found:      C, 68.85;   H, 8.19;  N, 7.72.                                    ______________________________________                                    

Compound 16

2-Diethylaminoethyl S-(R*,S*)!-4- 3,3-diethyl-1-1-(4-methyl-phenyl)butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoate

    ______________________________________                                        Analysis:   C.sub.32 H.sub.45 N.sub.3 O.sub.6                                 Calc:       C, 69.66;   H, 8.22;  N, 7.62.                                    Found:      C, 69.37;   H, 8.41;  N, 7.51.                                    ______________________________________                                    

Compound 17

2-(1- 4-morpholino!ethyl) S-(R*,S*)!-4- 3,3-diethyl-1-1-(4-methyl-phenyl)butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoate

    ______________________________________                                        Analysis:       C.sub.32 H.sub.43 N.sub.3 O.sub.6                             Calc:           C, 67.94; H, 7.66; N, 7.43.                                   Found:          C, 67.67; H, 7.90; N, 7.26.                                   ______________________________________                                    

Compound 18

4-dimethylaminobutyl S-(R*,S*)!-4- 3,3-diethyl-1-1-(4-methyl-phenyl)butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoate

    ______________________________________                                        Analysis:       C.sub.32 H.sub.45 N.sub.3 O.sub.5 + 0.2 H.sub.2 O             Calc:           C, 69.21; H, 8.24; N, 7.56.                                   Found:          C. 69.35; H, 8.24; N, 7.29.                                   ______________________________________                                    

Compound 20

2-dimethylamino-2-methyl-1-propyl S-(R*,S*)!-4- 3,3-diethyl-1-1-(4-methyl-phenyl)butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoate

    ______________________________________                                        Analysis:       C.sub.32 H.sub.45 N.sub.3 O.sub.5                             Calc:           C, 69.66; H, 8.22; N, 7.62.                                   Found:          C, 69.52; H, 8.47; N, 7.59.                                   ______________________________________                                    

Compound 21

2-(diisopropylamino)ethyl S-(R*,S*)!-4- 3,3-diethyl-1-1-(4-methyl-phenyl)butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoate

    ______________________________________                                        Analysis:       C.sub.34 H.sub.49 N.sub.3 O.sub.5                             Calc:           C, 70.44; H, 8.52; N, 7.25.                                   Found:          C, 70.28; H, 8.76; N, 7.13.                                   ______________________________________                                    

Compound 22

Benzyl S-(R*,S*)!-4- 2- 4- 3,3-di-ethyl-1-1-(4-methylphenyl)butyl!-amino!carbonyl!-4-oxo-2-azetidinyl!oxy!-benzoyl!oxy!-ethyl!-1-Piperazine-carboxylate

    ______________________________________                                        Analysis:       C.sub.40 H.sub.50 N.sub.4 O.sub.7                             Calc:           C, 68.75; H, 7.21; N, 8.02.                                   Found:          C, 68.39; H, 7.30; N, 7.84.                                   ______________________________________                                    

Compound 23

2-(dibutylamino)ethyl S-(R*,S*)!-4- 3,3-diethyl-1-1-(4-methyl-phenyl)-butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoate,

    ______________________________________                                        Analysis:       C.sub.36 H.sub.53 N.sub.3 O.sub.5                             Calc:           C, 71.14; H, 8.79; N, 6.91.                                   Found:          C, 71.00; H, 9.03; N, 6.81.                                   ______________________________________                                    

Compound 24

S-(R*,S*)!-6-(dimethylamino)hexyl-4- 3,3-diethyl-1-1-(4-methyl-phenyl)-butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!-benzoate

    ______________________________________                                        Analysis:       C.sub.34 H.sub.49 N.sub.3 O.sub.5 + 1 H.sub.2 O               Calc:           C, 68.31; H, 8.60; N, 7.03.                                   Found:          C, 68.34; H, 8.29; N, 6.86.                                   ______________________________________                                    

Compound 26

2-(4-methyl-1-piperazinyl)ethyl S-(R*,S*)!4- 3,3-diethyl-1-1-(4-methyl-phenyl)butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoate,

    ______________________________________                                        Analysis:       C.sub.33 H.sub.46 N.sub.4 O.sub.5 + 0.8 H.sub.2 O             Calc:           C, 66.82; H, 8.09; N, 9.44.                                   Found:          C, 67.28; H, 8.10; N, 8.96.                                   ______________________________________                                    

Compound 28

2-(diphenylamino)ethyl S-(R*,S*)!-4- 3,3-diethyl-1-1-(4-methylphenyl)-butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoate,

    ______________________________________                                        Analysis:       C.sub.40 H.sub.45 N.sub.3 O.sub.5 + 1.4 H.sub.2 O             Calc:           C, 71.40; H, 7.16; N, 6.25.                                   Found:          C, 71.62; H, 6.99; N, 5.99.                                   ______________________________________                                    

Compound 29

2-(di-2-propenylamino)ethyl S-(R*,S*)!-4- 3,3-diethyl-1-1-(4-methylphenyl)-butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoate,

    ______________________________________                                        Analysis:       C.sub.34 H.sub.45 N.sub.3 O.sub.5                             Calc:           C, 70.93; H, 7.88; N, 7.30.                                   Found:          C, 71.18; H, 8.06; N, 7.34.                                   ______________________________________                                    

Compound 30

2-(dimethylamino)-2-phenylethyl S-(R*,-S*)!-4- 3,3-diethyl-1-1-(4-methyl-phenyl)butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoate,

    ______________________________________                                        Analysis:       C.sub.36 H.sub.45 N.sub.3 O.sub.5                             Calc.           C, 72.09; H, 7.56; N, 7.00.                                   Found:          C, 71.75; H, 7.67; N, 6.70.                                   ______________________________________                                    

Compound 31

2- methyl(phenylmethyl)amino!ethyl S-(R*,S*)!-4- 3,3-diethyl-1-1-(4-methyl-phenyl)butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoate,

When S-(R*,S*)!-4- 3,3-diethyl-1- 1-(4-methylphenyl)butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!-2,6-dimethyl benzoic acidis used in place of S(R*,S*)!-4- 3,3-diethyl-1-1-(4-methylphenyl)-butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzoicacid in the procedure of Example 3A and allowed to react with theappropriate amino alcohols the following esters are obtained.

Compound 304

2-(dimethylamino)ethyl S,(R*,S*)!-4- 3,3-diethyl-1-1-(4-methylphenyl)-butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!-2,6-dimethyl-benzoate,

Compound 305

2-(diethylamino)ethyl S-(R*,S*)!-4- 3,3-diethyl-1-1-(4-methylphenyl)-butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!-2,6-dimethyl-benzoate,

Compound 306

2- bis(1-methylethyl)amino!-ethyl S-(R*S*)!4- 3,3-diethyl-1-1-(4-methylphenyl)butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!-2,6-dimethylbenzoate.

Treatment of the acid S-(R*,S*)!-4- 3,3-diethyl-1-1-(4-methylphenyl)butyl!amino!carbonyl!-4-oxo-2-azetidinyl!oxy!benzeneaceticacid with oxalyl chloride according to the procedure of Example 3Aaffords the corresponding acid chloride which when allowed to react withthe appropriate amino alcohol according to the procedure of Example 8gives the following amino esters:

Compound 32

    ______________________________________                                        Analysis:       C.sub.31 H.sub.43 N.sub.3 O.sub.5                             Calc:           C, 69.25; H, 8.06; N, 7.82.                                   Found:          C, 69.02; H, 7.86; N, 7.74.                                   ______________________________________                                    

Compound 33

    ______________________________________                                        Analysis:       C.sub.32 H.sub.45 N.sub.3 O.sub.5                             Calc:           C, 69.66; H, 8.22; N, 7.62.                                   Found:          C, 69.10; H, 8.17; N, 7.50.                                   ______________________________________                                    

Compound 34

    ______________________________________                                        Analysis:       C.sub.33 H.sub.47 N.sub.3 O.sub.5                             Calc:           C, 70.06; H, 8.38; N, 7.43.                                   Found:          C, 69.70; H, 8.41; N, 7.05.                                   ______________________________________                                    

Compound 35

    ______________________________________                                        Analysis:       C.sub.33 H.sub.45 N.sub.3 O.sub.6                             Calc:           C, 68.37; H, 7.82; N, 7.25.                                   Found:          C, 68.55; H, 8.19; N, 7.08.                                   ______________________________________                                    

Compound 36

    ______________________________________                                        Analysis:       C.sub.32 H.sub.45 N.sub.3 O.sub.5                             Calc:           C, 69.66; H, 8.22; N, 7.62.                                   Found:          C, 69.60; H, 8.49; N, 7.55.                                   ______________________________________                                    

EXAMPLE 9

To a solution of 0.247 g of Compound 1 in 2 ml of ethyl acetate is added0.125 gm of m-chloroperoxy benzoic acid. After 30 minutes at roomtemperature the reaction mixture is concentrated in vacuo.Chromatography of the residue on silica gel using methylenechloride/methanol/water 85/15/1.5 gives the desired N-oxide Compound 15.

    ______________________________________                                        Analysis:       C.sub.30 H.sub.41 N.sub.3 O.sub.8 + 1.4 H.sub.2 O             Calc:           63.79; H, 7.82; N, 7.44                                       Found:          63.89; H, 7.85; N, 7.27                                       ______________________________________                                    

EXAMPLE 10 S-(R*,S*)! 2- 4-2-(dimethylamino)-ethyl!amino!-carbonyl!phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)-butyl!-4-oxo-1-azetidinecarboxamide.

To a solution of 0.104 g carbonyldiimidazole in 2 ml methylene chlorideis added a solution of 0.227 g ofS-(R*,S*)!-4-((3,3-diethyl-1-((-1-(4-methylphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)-oxy)benzoicacid in 3 ml methylene chloride. The mixture is stirred at ambienttemperature for 30 minutes at which time 0.100 g ofN,N-dimethylethylenediamine is added. After stirring overnight at roomtemperature the reaction mixture is poured into benzene (50 ml) andwashed with water. The organic layer is separated, dried through sodiumsulfate and concentrated in vacuo. Silica gel chromatography using 5%methanol in methylene chloride yields 0.160 g of 2- 4-2-(dimethylamino)-ethyl!amino!carbonyl!phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide. (Compound 73).

    ______________________________________                                        Analysis:       C.sub.30 H.sub.42 N.sub.4 O.sub.4 + 0.4 H.sub.2 O             Calc:           C, 68.00; H, 8.14; N, 10.57.                                  Found:          C, 68.01; H, 8.18; N, 10.62.                                  ______________________________________                                    

EXAMPLE 11 A.(S-(R*,S*))-4-((3,3-diethyl-1-((1-(4-methyl-phenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)-oxy)-benzoylchloride.

To a solution of 0.150 g of S-(R*,S*)!4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)-carbonyl)-4-oxo-2-azetidinyl)oxy)benzoicacid in 5 ml methylene chloride containing a catalytic amount ofdimethylformamide is added 0.5 ml of oxalyl chloride. The mixture isstirred at room temperature for 30 minutes and then concentrated invacuo to yield(S-(R*,S*))-4-((3,3-diethyl-1-((1-(4-methyl-phenyl)-butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)-benzoylchloride.

B. S-(R*,S*)!2- 4-2-(dimethylamino)ethyl!methyl-amino!carbonyl!-phenoxy!-3,3-diethyl-N-1-(4-methylphenyl!butyl!-4-oxo-1-azetidinecarboxamide.

The above acid chloride is dissolved in 3 ml methylene chloride and asolution of 0.20 gm of N,N,N'-trimethylethylenediamine in 2 ml methylenechloride is added. The mixture is stirred overnight and thenconcentrated in vacuo. The residue is extracted between ethyl acetateand saturated sodium bicarbonate solution. The organic layer is driedthrough sodium sulfate and concentrated in vacuo. Silica gelchromatography of the residue (5% methanol in methylene chloride)affords 0.117 g of S-(R*,S*)!-2- 4-2-(dimethylamino)ethyl!methylamino!carbonyl!-phenoxy!-3,3-diethyl-N-1-(4-methylphenyl!butyl-4-oxo-1-azetidinecarboxamide. (Compound 75).

    ______________________________________                                        Analysis:       C.sub.31 H.sub.44 N.sub.4 O.sub.4 + 0.5H.sub.2 O              Calc:           C, 68.23; H, 8.31; N, 10.27.                                  Found:          C, 68.20; H, 8.41; N, 10.10.                                  ______________________________________                                    

When N,N,N'-trimethylethylenediamine of Example 11b is replaced by theappropriate amines, there is obtained the corresponding amides.

1) Compound 76

    ______________________________________                                        Analysis:       C.sub.32 H.sub.46 N.sub.4 O.sub.4                             Calc:           C, 69.79; H, 8.42; N, 10.17.                                  Found:          C, 69.02; H, 8.60; N, 9.54.                                   ______________________________________                                    

2) Compound 77

    ______________________________________                                        Analysis:       C.sub.32 H.sub.46 N.sub.4 O.sub.4 + 0.75 H.sub.2 O            Calc:           C, 68.12; H, 8.49; N; 9.93.                                   Found:          C, 68.22; H, 8.48; N, 10.17.                                  ______________________________________                                    

3) Compound 78

    ______________________________________                                        Analysis:       C.sub.32 H.sub.44 N.sub.4 O.sub.5                             Calc:           C, 68.06; H, 7.85; N, 9.92.                                   Found:          C, 67.84; H, 8,07; N, 9.62.                                   ______________________________________                                    

4) Compound 79

    ______________________________________                                        Analysis:       C.sub.33 H.sub.46 N.sub.4 O.sub.5 + H.sub.2 O                 Calc:           C, 66.42; H, 8.11; N, 9.39.                                   Found:          C, 66.73; H, 8.19; N, 9.23.                                   ______________________________________                                    

5) Compound 80

    ______________________________________                                        Analysis:       C.sub.35 H.sub.52 N.sub.4 O.sub.6                             Calc:           C, 67.28; H, 8.39; N, 8.97.                                   Found:          C, 67.08; H, 8.77; N, 8.41.                                   ______________________________________                                    

6) Compound 81

    ______________________________________                                        Analysis:       C.sub.33 H.sub.48 N.sub.4 O.sub.4 + H.sub.2 O                 Calc:           C, 68.01; H, 8.65; N, 9.61.                                   Found:          C, 68.42; H, 8.59; N, 9.17.                                   ______________________________________                                    

7) Compound 82

    ______________________________________                                        Analysis:       C.sub.36 H.sub.46 N.sub.4 O.sub.4 + 0.5H.sub.2 O              Calc:           C, 71.14; H, 7.79; N, 9.21.                                   Found:          C, 71.41; H, 7.68; N, 9.10.                                   ______________________________________                                    

8) Compound 83

    ______________________________________                                        Analysis:       C.sub.32 H.sub.46 N.sub.4 O.sub.4 + 1.2H.sub.2 O              Calc:           C, 67.15; H, 8.52; N, 9.79.                                   Found:          C, 67.21; H, 8.26; N, 9.47.                                   ______________________________________                                    

9) Compound 84

10) Compound 86

    ______________________________________                                        Analysis:       C.sub.35 H.sub.52 N.sub.4 O.sub.4                             Calc:           C, 70.91; H, 8.84; N, 9.45.                                   Found:          C, 70.37; H, 8.84; N, 8.77.                                   ______________________________________                                    

11) Compound 89

    ______________________________________                                        Analysis:       C.sub.31 H.sub.39 N.sub.5 O.sub.4 + 0.7H.sub.2 O              Calc:           C, 66.71; H, 7.29; N, 12.54.                                  Found:          C, 66.91; H, 7.40; N, 12.14.                                  ______________________________________                                    

12) Compound 90

    ______________________________________                                        Analysis:       C.sub.33 H.sub.46 N.sub.4 O.sub.4 + 0.8H.sub.2 O              Calc:           C, 68.67; H, 8.31; N, 9.70.                                   Found:          C, 68.82; H, 8.11; N, 9.70.                                   ______________________________________                                    

13) Compound 91

    ______________________________________                                        Analysis:       C.sub.34 H.sub.48 N.sub.4 O.sub.4 + 0.3H.sub.2 O              Calc:           C, 70.11; H, 8.41; N, 9.61.                                   Found:          C, 70.17; H, 8.64; N, 9.33.                                   ______________________________________                                    

14) Compound 92

    ______________________________________                                        Analysis:       C.sub.30 H.sub.42 N.sub.4 O.sub.4 + 1.2H.sub.2 O              Calc:           C, 66.14; H, 8.22; N, 10.29.                                  Found:          C, 66.18; H, 8.12; N, 10.31.                                  ______________________________________                                    

15) Compound 93

    ______________________________________                                        Analysis:       C.sub.32 H.sub.44 N.sub.4 O.sub.6 + 0.3H.sub.2 O              Calc:           C, 65.57; H, 7.67; N, 9.56.                                   Found:          C, 65.72; H, 7.50; N, 9.34.                                   ______________________________________                                    

16) Compound 94

    ______________________________________                                        Analysis:       C.sub.32 H.sub.44 N.sub.4 O.sub.4 + 0.3H.sub.2 O              Calc:           C, 70.04; H, 8.08; N, 10.21.                                  Found:          C, 70.34; H, 8.90; N, 8.93.                                   ______________________________________                                    

17) Compound 95

    ______________________________________                                        Analysis:       C.sub.33 H.sub.46 N.sub.4 O.sub.4 + .5H.sub.2 O               Calc:           C, 69.32; H, 8.28; N, 9.80.                                   Found:          C, 69.41; H, 8.25; N, 9.58.                                   ______________________________________                                    

18) Compound 99

    ______________________________________                                        Analysis:       C.sub.38 H.sub.54 N.sub.4 O.sub.4 + 1.5H.sub.2 O              Calc:           C, 69.37; H, 8.72; N, 8.51                                    Found:          C, 69.48; H, 8.44; N, 8.36                                    ______________________________________                                    

19) Compound 102

    ______________________________________                                        Analysis:       C.sub.40 H.sub.49 N.sub.5 O.sub.6 + 1.0 H.sub.2 O             Calc:           C, 67.30; H, 7.20; N, 9.81                                    Found:          C, 67.50; H, 7.24; N, 9.53                                    ______________________________________                                    

20) Compound 104

    ______________________________________                                        Analysis:       C.sub.32 H.sub.41 N.sub.5 O.sub.4 + 0.75H.sub.2 O             Calc:           C, 67.04; H, 7.47; N, 12.21.                                  Found:          C, 67.16; H, 7.56; N, 11.95.                                  ______________________________________                                    

21) Compound 105

    ______________________________________                                        Analysis:       C.sub.32 H.sub.44 N.sub.4 O.sub.5 + 0.5H.sub.2 O              Calc:           C, 66.99; H, 7.91; N, 9.77.                                   Found:          C, 67,00; H, 8.25; N, 9.50.                                   ______________________________________                                    

22) Compound 106

    ______________________________________                                        Analysis:       C.sub.32 H.sub.45 N.sub.5 O.sub.5 + 0.8H.sub.2 O              Calc:           C, 64.69; H, 7.90; N, 11.78.                                  Found:          C, 64.93; H, 8.25; N, 11.12.                                  ______________________________________                                    

23) Compound 107

    ______________________________________                                        Analysis:       C.sub.31 H.sub.44 N.sub.3 O.sub.6 S + 0.3H.sub.2 O            Calc:           C, 61.42; H, 7.41; N, 9.24.                                   Found:          C, 61.43; H, 7.54; N, 9.05.                                   ______________________________________                                    

24) Compound 110

    ______________________________________                                        Analysis:       C.sub.35 H.sub.44 N.sub.4 O.sub.4                             Calc:           C, 71.89; H, 7.58; N, 9.58.                                   Found:          C, 71.65; H, 7.55; N, 9.34.                                   ______________________________________                                    

25) Compound 111

    ______________________________________                                        Analysis:   C.sub.34 H.sub.42 N.sub.4 O.sub.4 + 0.5H.sub.2 O                  Calc:       C, 70.44;   H, 7.47,  N, 9.66.                                    Found:      C, 70.82,   H, 7.46;  N, 9.20.                                    ______________________________________                                    

26) Compound 113

    ______________________________________                                        Analysis:   C.sub.34 H.sub.42 N.sub.4 O.sub.4 + 0.3H.sub.2 O                  Calc:       C, 70.88;   H, 7.45;  N, 9.72.                                    Found:      C, 71.12;   H, 7.44;  N, 9.32.                                    ______________________________________                                    

27) Compound 115

    ______________________________________                                        Analysis:   C.sub.34 H.sub.42 N.sub.4 O.sub.4 + 0.7H.sub.2 O                  Calc:       C, 69.99;   H, 7.50;  N, 9.60.                                    Found:      C, 70.14, H, 7.63;                                                                        N, 9.25.                                              ______________________________________                                    

28) Compound 116

    ______________________________________                                        Analysis:   C.sub.34 H.sub.46 N.sub.4 O.sub.4 + 1.4H.sub.2 O                  Calc:       C, 68.06;   H, 8.19;  N, 9.33.                                    Found:      C, 68.40;   H, 8.14;  N, 8.87.                                    ______________________________________                                    

29) Compound 117

    ______________________________________                                        Analysis:   C.sub.40 H.sub.51 N.sub.5 O.sub.6 + 0.6H.sub.2 O                  Calc:       C, 67.79;   H, 7.42;  N, 9.88.                                    Found:      C, 67.81;   H, 7.58;  N, 9.76.                                    ______________________________________                                    

30) Compound 118

    ______________________________________                                        Analysis:   C.sub.33 H.sub.47 N.sub.5 O.sub.4 + 0.7H.sub.2 O                  Calc:       C, 67.14;   H, 8.26;  N, 11.86                                    Found:      C, 67.54;   H, 8.51;  N, 11.28.                                   ______________________________________                                    

31) Compound 119

    ______________________________________                                        Analysis:   C.sub.35 H.sub.48 N.sub.4 O.sub.4 + 1.25H.sub.2 O                 Calc:       C, 68.76;   H, 8.32;  N, 9.16.                                    Found:      C, 69.07;   H, 8.19;  N, 8.75.                                    ______________________________________                                    

32) Compound 121

    ______________________________________                                        Analysis:   C.sub.34 H.sub.48 N.sub.4 O.sub.4 + 1H.sub.2 O                    Calc:       C, 68.66;   H, 8.47;  N, 9.42.                                    Found:      C, 69.02;   H, 8.32;  N, 9.06.                                    ______________________________________                                    

33) Compound125

    ______________________________________                                        Analysis:   C.sub.37 H.sub.48 N.sub.4 O.sub.4 + 0.5H.sub.2 O                  Calc:       C, 71.47;   H, 7.94;  N, 9.01                                     Found:      C, 71.65;   H, 7.91;  N, 8.73.                                    ______________________________________                                    

34) Compound 126

    ______________________________________                                        Analysis:   C.sub.41 H.sub.54 N.sub.4 O.sub.5 + 2H.sub.2 O                    Calc:       C, 68.83;   H, 8.25;  N, 7.64.                                    Found:      C, 69.03;   H, 7.79;  N, 7.50.                                    ______________________________________                                    

35) Compound 132

    ______________________________________                                        Analysis:   C.sub.35 H.sub.5 ON.sub.4 O.sub.4                                 Calc:       C, 71.15;   H, 8.53;  N, 9.48.                                    Found:      C, 70.90;   H, 8.74;  N, 9.12.                                    ______________________________________                                    

36) Compound 133

    ______________________________________                                        Analysis:   C.sub.40 H.sub.52 N.sub.4 O.sub.4 + 0.9H.sub.2 O                  Calc:       C, 71.80;   H, 8.10;  N, 8.37.                                    Found:      C, 71.86;   H, 8.17;  N, 8.18.                                    ______________________________________                                    

37) Compound 137

    ______________________________________                                        Analysis:   C.sub.37 H.sub.48 N.sub.4 O.sub.4 + 0.8H.sub.2 O                  Calc.       C, 70.85;   H, 7.97;  H, 8.93.                                    Found:      C, 71.01;   H, 7.97;  N, 8.54.                                    ______________________________________                                    

38) Compound 139

    ______________________________________                                        Analysis:   C.sub.39 H.sub.51 N.sub.5 O.sub.4 + 0.8H.sub.2 O                  Calc:       C, 70.09;   H, 7.93;  N, 10.48.                                   Found:      C, 70.18;   H, 7.79;  N, 10.42.                                   ______________________________________                                    

39) Compound 142

    ______________________________________                                        Analysis:   C.sub.38 H.sub.55 N.sub.5 O.sub.6                                 Calc:       C, 67.33;   H, 8.18;  N, 10.33.                                   Found:      C, 67.02;   H, 8.31;  N, 9.89.                                    ______________________________________                                    

40) Compound 143

    ______________________________________                                        Analysis:   C.sub.34 H.sub.51 N.sub.5 O.sub.4                                 Calc:       C, 68.77;   H, 8.66;  N, 11.80.                                   Found:      C, 68.57;   H, 8.50;  N, 11.53                                    ______________________________________                                    

41) Compound 144

    ______________________________________                                        Analysis:   C.sub.38 H.sub.59 N.sub.5 O.sub.4 + 0.4H.sub.2 O                  Calc:       C, 69.45;   H, 9.17;  N, 10.65.                                   Found:      C, 69.69;   H, 9.02;  N, 10 35.                                   ______________________________________                                    

42) Compound 145

    ______________________________________                                        Analysis:   C.sub.36 H.sub.47 N.sub.5 O.sub.4 + H.sub.2 O                     Calc:       C, 68.44;   H, 7.82;  N, 11.08                                    Found:      C, 68.69;   H, 7.74;  N, 10.76.                                   ______________________________________                                    

43) Compound 148

    ______________________________________                                        Analysis:   C.sub.36 H.sub.47 N.sub.5 O.sub.4 + 0.4H.sub.2 O                  Calc:       C, 69.62;   H, 7.56;  N, 11.27.                                   Found:      C, 69.79;   H, 7.70;  N, 11.12.                                   ______________________________________                                    

44) Compound 149

    ______________________________________                                        Analysis:   C.sub.39 H.sub.50 N.sub.4 O.sub.4 + 0.4H.sub.2 O                  Calc:       C, 72.50;   H, 7.93;  N, 8.67                                     Found:      C, 72.44;   H, 7.99;  N, 8.87.                                    ______________________________________                                    

45) Compound 150

    ______________________________________                                        Analysis:   C.sub.36 H.sub.47 N.sub.5 O.sub.4 + 0.3H.sub.2 O                  Calc.       C, 69.83;   H, 7.74;  N, 11.31.                                   Found:      C, 69.93;   H, 7.65,  N, 11.10.                                   ______________________________________                                    

46) Compound 151

    ______________________________________                                        Analysis:   C.sub.33 H.sub.47 N.sub.5 O.sub.4                                 Calc:       C, 68.60;   H, 8.20;  N, 12.12.                                   Found:      C, 68.40;   H, 8.16;  N, 11.90.                                   ______________________________________                                    

47) Compound 245

    ______________________________________                                        Analysis:   C.sub.36 H.sub.44 N.sub.4 O.sub.4                                 Calc:       C, 72.46;   H, 7.43;  N, 9.39                                     Found:      C, 72.49;   H, 7.49;  N, 9.25                                     ______________________________________                                    

48) Compound 246

    ______________________________________                                        Analysis:   C.sub.37 H.sub.46 N.sub.4 O.sub.4 + 0.25H.sub.2 O                 Calc:       C, 72.26;   H, 7.61;  N, 9.10.                                    Found:      C, 72.35;   H, 7.83;  N, 8.73.                                    ______________________________________                                    

49) Compound 154

    ______________________________________                                        Analysis:       C.sub.35 H.sub.48 N.sub.4 O.sub.4 + 0.8H.sub.2 O              Calc:           C, 69.70; H, 8.29; N, 9.29                                    Found:          C, 69.65; H, 8.27, N, 9.35.                                   ______________________________________                                    

50) Compound 158

    ______________________________________                                        Analysis:       C.sub.35 H.sub.48 N.sub.4 O.sub.4 + 0.5H.sub.2 O              Calc:           C, 73.29; H, 7.65; N, 8.33.                                   Found:          C, 73.71, H, 7.75, N, 7.75.                                   ______________________________________                                    

51) Compound 159

    ______________________________________                                        Analysis:       C.sub.35 H.sub.48 N.sub.4 O.sub.4                             Calc:           C, 73.09; H, 7.66; N, 8.31.                                   Found:          C, 73.40; H, 7.75; N, 7.80.                                   ______________________________________                                    

52) Compound 160

    ______________________________________                                        Analysis:       C.sub.38 H.sub.48 N.sub.4 O.sub.4 + 1.0H.sub.2 O              Calc:           C, 70.78; H, 8.12; N, 8.68.                                   Found:          C, 71.00; H, 8.05; N, 8.59.                                   ______________________________________                                    

53) Compound 161

    ______________________________________                                        Analysis:       C.sub.43 H.sub.52 N.sub.4 O.sub.4 + 1H.sub.2 O                Calc:           C, 73.05; H, 7.70; N, 7.92.                                   Found:          C, 73.29; H, 7.95; N, 7.37.                                   ______________________________________                                    

54) Compound 166

    ______________________________________                                        Analysis:       C.sub.33 H.sub.46 N.sub.4 O.sub.4 + 1.5H.sub.2 O              Calc.           C, 67.20; H, 8.37; N, 9.50                                    Found:          C, 67.38; H, 7.98; N, 9.41.                                   ______________________________________                                    

55) Compound 171

    ______________________________________                                        Analysis:       C.sub.36 H.sub.52 N.sub.4 O.sub.6 + 1.6H.sub.2 O              Calc:           C, 64.95; H, 8.36; N, 8.41.                                   Found:          C, 65.26; H, 8.15; N, 8.07.                                   ______________________________________                                    

56) Compound 177

    ______________________________________                                        Analysis:       C.sub.38 H.sub.47 N.sub.5 O.sub.4                             Calc:           C, 71.56; H, 7.43; N, 10,98.                                  Found:          C, 71.64; H, 7.62; N, 10.93.                                  ______________________________________                                    

57) Compound 178

    ______________________________________                                        Analysis:       C.sub.38 H.sub.50 N.sub.4 O.sub.4                             Calc:           C, 72.81; H, 8.04; N, 8.94.                                   Found:          C, 72.96; H, 8.17; N, 8.83.                                   ______________________________________                                    

58) Compound 179

    ______________________________________                                        Analysis:       C.sub.38 H.sub.47 N.sub.5 O.sub.4                             Calc:           C, 71.56; H, 7.43; N, 10.98.                                  Found:          C, 72.00; H, 7.55; N, 10.87.                                  ______________________________________                                    

59) Compound 180

    ______________________________________                                        Analysis:       C.sub.38 H.sub.47 F.sub.3 N.sub.4 O.sub.4                     Calc:           C, 67.04; H, 6.96; N, 8.23.                                   Found:          C, 67.02; H, 7.25; N, 8.23.                                   ______________________________________                                    

60) Compound 181

    ______________________________________                                        Analysis:       C.sub.38 H.sub.47 F.sub.3 N.sub.4 O.sub.4                     Calc:           C, 67.04; H, 6.96; N, 8.23                                    Found:          C, 66.63; H, 6.98; N, 7.94.                                   ______________________________________                                    

61) Compound 182

    ______________________________________                                        Analysis:       C.sub.37 H.sub.47 F N.sub.4 O.sub.4                           ______________________________________                                        Calc:           C, 70.45; H, 7.51; N, 8.88                                    Found:          C, 70.28; H, 7.74; N, 8.82.                                   ______________________________________                                    

62) Compound 185

    ______________________________________                                        Analysis:       C.sub.34 H.sub.48 N.sub.4 O.sub.4                             ______________________________________                                        Calc:           C, 70.80; H, 8.39; N, 9.71                                    Found:          C, 70.44; H, 8.45; N, 9.51.                                   ______________________________________                                    

63) Compound 186

    ______________________________________                                        Analysis:       C.sub.37 H.sub.48 N.sub.4 O.sub.4  +0.8H.sub.2 O              ______________________________________                                        Calc:           C, 70.85; H, 7.97; N, 8.93                                    Found:          C, 71.12; H, 8.25; N, 8.45.                                   ______________________________________                                    

64) Compound 191

    ______________________________________                                        Analysis:       C.sub.42 H.sub.51 N.sub.5 O.sub.4  +.5CH.sub.2 C1.sub.2       ______________________________________                                        Calc:           C, 69.78; H, 7.16; N, 9.58                                    Found:          C, 69.75; H, 7.31; N, 9.68.                                   ______________________________________                                    

65) Compound 203

    ______________________________________                                        Analysis:       C.sub.37 H.sub.47 N.sub.4 O.sub.4  +1.1H.sub.2 O              ______________________________________                                        Calc:           C, 68.31; H, 7.62; N, 8.61                                    Found:          C, 68.32; H, 7.57; N, 8.53.                                   ______________________________________                                    

66) Compound 204

    ______________________________________                                        Analysis:       C.sub.37 H.sub.47 ClN.sub.4 O.sub.4                           ______________________________________                                        Calc:           C, 68.66; H, 7.32; N, 8.66.                                   Found:          C, 68.32, H, 7.48; N, 8.42.                                   ______________________________________                                    

67) Compound 205

    ______________________________________                                        Analysis:       C.sub.38 H.sub.50 N.sub.4 O.sub.5  +0.7H.sub.2 O              ______________________________________                                        Calc:           C, 69.63; H, 7.90; N, 8.54.                                   Found:          C, 69.72; N, 7.91; N, 8.54.                                   ______________________________________                                    

68) Compound 206

    ______________________________________                                        Analysis:       C.sub.39 H.sub.52 N.sub.4 O.sub.6  +0.8H.sub.2 O              ______________________________________                                        Calc:           C, 68.15; H, 7.86; N, 8.15                                    Found:          C, 68.01; H, 8.02; N, 8.15.                                   ______________________________________                                    

EXAMPLE 12 A) S-(R*,S*)3,3-Diethyl-2- 4-2-(4-hydroxy-1-piperidinyl)ethyl!amino!carbonyl!phenoxy!-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide

When 1-(2-aminoethyl)-4-benzyloxypiperidine is used in place ofN,N,N'-trimethylethylene diamine in the procedure of Example 11b thereis obtained S-(R*,S*)!3,3-diethyl-2- 4-2-(4-benzyloxy-1-piperidinyl!ethyl!amino!carbonyl!phenoxy!-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide.

B) S-(R+,S*)!3,3-diethyl-2- 4-2-(4-hydroxy-1-piperidinyl)ethyl!amino!carbonyl!phenoxy!-N-1-(4-methyl-phenyl)butyl!-4-oxo-1-azetidine-carboxamide

A solution of the amide from step A above in 10 ml of glacial aceticacid containing 22 mg of 10% Pd/C is hydrogenated under 42 lb hydrogenpressure. When TLC indicate completion of the reaction, the mixture isfiltered and concentrated in vacuo after the addition of 50 ml toluene.The residue is dissolved in ethyl acetate, washed with saturated sodiumbicarbonate solution. The organic layer is dried with sodium sulfate andconcentrated in vacuo. The residue is chromatographed on 15 g silica gelusing 5% methanol in methylene chloride and yields 96 mg of

S-(R+,S*)!-3,3-diethyl-2- 4-2-(4-hydroxy-1-piperidinyl)ethyl!amino!carbonyl!phenoxy!-N-1-(4-methyl-phenyl)butyl!-4-oxo-1-azetidine-carboxamide

    ______________________________________                                        Analysis:       C.sub.33 H.sub.46 N.sub.4 O.sub.5  +1.3H.sub.2 O              ______________________________________                                        Calc:           C, 65.83; H, 8.13; N, 9.30                                    Found:          C, 66.10; H, 8.06; N, 8.91                                    ______________________________________                                    

When 1-(2-aminoethyl)-4-benzyloxypiperidine is replaced in the procedureof Example 12 by the appropriate amines, the following compounds 123,124, 129, 131 and 138 are obtained, for example:

1) Compound 129

    ______________________________________                                        Analysis:       C.sub.34 H.sub.48 N.sub.4 O.sub.5                             ______________________________________                                        Calc:           C, 68.89; H, 8.16; N, 9.45                                    Found:          C, 68.68; H, 8.18; N, 8.65                                    ______________________________________                                    

2) Compound 131

    ______________________________________                                        Analysis:       C.sub.32 H.sub.44 N.sub.4 O.sub.5  +1H.sub.2 O                ______________________________________                                        Calc:           C, 65.92; H, 7.96; N, 9.61                                    Found:          C, 66.07; H, 7.86; N, 9.45                                    ______________________________________                                    

3) Compound 138

    ______________________________________                                        Analysis:       C.sub.33 H.sub.46 N.sub.4 O.sub.5  +0.5H.sub.2 O              ______________________________________                                        Calc:           C, 67.43; H, 8.06; N, 9.53                                    Found:          C, 67.61; H, 8.06; N, 9.37                                    ______________________________________                                    

Diamine Intermediates

The diamines used to prepare the amino amides described herein werecommercially available or prepared according to the following routes##STR29##

EXAMPLE 13 A N-cyanomethylhomopiperazine.

To a solution of 1.98 g homopiperazine in 50 ml acetone is added 4.25 gof powdered anhydrous sodium carbonate and 1.3 ml of chloroacetonitrite.After 24 hrs the reaction mixture is filtered and the filter cake washedwith 100 ml acetone. The combined filtrates are concentrated in vacuoand the residue chromatographed on silica gel using methylene chlorideas the eluent. The yield of N-cyanomethyl homopiperazine is 2.69 g.

B. N-(2-aminoethyl)homopiperazine.

To a suspension of 1.02 g lithium aluminum hydride in 50 ml of ether isslowly added a solution of 2.65 gm N-cyanomethyl homopiperazine in 25 mlether. After the addition in complete the mixture is heated at refluxfor 1 hour, then cooled to room temperature and quenched carefully with1 ml water, 1 ml of 15% sodium hydroxide solution and 3 ml water. Themixture is filtered through sodium sulfate, the filter cake washed wellwith ether and the combined filtrates concentrated in vacuo to yield2.60 g. N-(2-aminoethyl)homopiperazine. ##STR30##

EXAMPLE 14 N-(2-methylaminoethyl)homopiperazine. A).N-(2-formamidoethyl)homopiperazine.

To a carefully prepared solution of 0.718 g of 60% sodium hydridedispension in 75 ml of absolute ethanol which has been cooled to 0° C.is added 7.3 ml of ethyl formate. After 5 minutes there is added asolution of 2.55 gm of N-(2-aminoethyl)homopiperazine in 25 ml absoluteethanol. The mixture is stirred at room temperature overnight. Saturatedsodium bicarbonate solution (15 ml) is then added and the reactionmixture is stirred with 150 ml ethyl acetate, filtered through MgSO₄ andthe filtrate concentrated in vacuo. Chromatography of the residue on 150gm silica gel using an eluent of methylene chloride/methanol/conc.ammonium hydroxide (95/5/0.5) gives 2.78 g ofN-(2-formamidoethyl)homopiperazine.

B). N-(2-methylaminoethyl)homopiperazine.

To a solution of 2.75 gm of N-(2-formamidoethyl)homopiperazine in 20 mlof dry THF under N₂ is added carefully 60 ml of borane THF solution.After the addition is complete the reaction mixture is heated to refluxfor 5 hours then stirred at room temperature overnight. The reactionmixture is quenched by the careful addition of 20 ml of 6N HCl followedby refluxing for 1 hour. The reaction mixture is cooled, 50 ml of wateradded and solid KOH added carefully to alkaline pH. Extraction withether gives the desired product N-(2-methylamino)homopiperazine.

EXAMPLE 15 ##STR31## A)N-benzyl-N,N'-dimethyl-N'-(2-phenylethyl)-ethylenediamine

A mixture of 0.900 gm N-benzyl-N,N'-dimethylethylenediamine, 1.10 gmpowdered sodium carbonate and 0.75 ml of 2-phenylethylbromide isrefluxed for 5 hours. An additional 0.25 ml of bromide is added duringthis time. The reaction mixture is then cooled and filtered. Thefilterate is concentrated in vacuo and the residue chromatographed onsilica gel using an eluent of CH₂ Cl₂ /CH₃ OH/NH₄ OH (97/3/0.3) to yield0.875 gm of N-benzyl-N,N'-dimethyl-N'-(2-phenylethyl)ethylenediamine.

B) N,N'-dimethyl-N-(2-phenylethyl)ethylenediamine.

To a solution 0.870 gmN-benzyl-N-N'-di-methyl-N'-(2-phenylethyl)ethylenediamine in 10 mlethanol and 5 ml acetic acid is added 0.18 gm Pd (OH)₂ /C. The mixtureis hydrogenated at 40 psi for 3.5 hours, then filtered and concentratedin vacuo. The residue is made akaline with 1N NaOH and extracted wellwith ethyl acetate (5×25 ml). The combined extracts are filtered throughsodium sulfate and concentrated to yieldN,N'-dimethyl-N-(2-phenyl-ethyl)ethylenediamine.

EXAMPLE 16 ##STR32## A)

A solution of 1.28 gm 1-(2-amino-ethyl)piperdine and 1.07 gmpyridine-3-carboxaldehyde in 40 ml of toluene is heated to reflux undera Dean Stark trap. After 10 ml toluene distilled over the NMR of analiquot indicated no aldehyde left. The reaction mixture wasconcentrated and the imine used directly in the next step.

B)

To a suspension of 0.380 gm of lithium aluminum hydride in 30 ml of dryTHE which has been cooled to -10° C. is added dropwise a solution of theabove imine in 20 ml of dry THE. After about 1 hour the cold reactionmixture is quenched by the addition of 5 ml of 5N NaOH, then dilutedwith 100 ml ether and 20 ml of water. The organic layer is separated,washed with brine, filtered thru sodium sulfate and concentrated to give2.17 gm of 1- 2-(3-pyridyl-methylamino)ethyl!-piperidine suitable foruse in subsequent reactions.

EXAMPLE 17 ##STR33##

To 7.50 gm of N,N'-dimethylethylenediamine which has been cooled in anice-ethanol bath is added portionwise over a 30 minute period 1.40 gm of3-picolyl chloride. After stirring cold for 1 hour after the addition iscompleted, the reaction mixture is concentrated in vacuo and the residuepartitioned between 50 ml of ether and 10 ml of 5N NaOH solution. Theorganic layer is separated and the aqueous layer extracted 2 times with50 ml of ether. The combined organic extracts are dried through sodiumsulfate and concentrated in vacuo. Chromatography on 150 gm silica gelusing CH₂ Cl₂ /CH₃ OH/NH₄αH (90/10/1) as eluent gives 0.930 g ofN,N'-dimethyl-N-(3-pyridylmethyl)ethylenediamine.

EXAMPLE 18 Amino Acid→diamine

A)

To an ice cooled solution of 2.29 N-CBZ-D-Proline in 50 ml of CHCl₂ isadded 1.35 gm 1-hydroxybenzotriazole hydrate followed by 2.06 gm ofdicyclohexylcarbodiimide. After 20 minutes, 0.85 ml of pyrrolidine isadded and the reaction mixture stirred overnight after which time it isfiltered and the filtrate concentrated in vacuo. The residue ispartitioned between 100 ml ethyl acetate and 50 ml of 2N hydrochloricacid. The organic layer is separated, washed with 50 ml of 1.0N sodiumhydroxide solution, dried through sodium sulfate and concentrated invacuo. Chromatography on 150 gm of silica gel using ethylacetate inhexanes (30-100%) as eluent gives 2.04 gm of the desired pyrrolidineamide

B)

To a solution of 1.519 gm of the amide (prepared in A) in 20 ml absoluteethanol is added 75 mg of 10% Pd on carbon catalyst. The mixture ishydrogenated at 40 psi for about an hour then filtrate and the filtrateconcentrated to yield D-proline pyrrolidine amide.

C)

To a suspension of 0.380 gm of lithium aluminum hydride in 15 ml of drytetrahydrofuran is carefully added a solution of the D-proline amide(prepared in B above) in 10 ml tetrahydrofuran. The mixture is refluxedfor 2 hrs then cooled and quenched with 2 ml of 2.5N sodium hydroxide.The mixture is filtered through a pad of sodium sulfate and the filtercake washed with 2×50 ml of ether. The combined filtrates areconcentrated in vacuo to yield 0.80 gm of desired2-(1-pyrrolidinylmethyl) pyrrolidine.

EXAMPLE 19 S-(R*,S*)!-2- 4-(4-Methyl)piperazin-1-yl!carbonyl!phenoxy!-((3,3-diethyl-N-1-(methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide

A solution ofS-(R*,S*)!4-(((3,3-diethyl-1-((4-methylphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoylchloride (3.8 mmol), prepared as in Example 11A, in 50 ml of methylenechloride was cooled in an ice bath and a solution of 0.70 gm ofN-methylpiperazine in 10 ml of methylene chloride was added over 5 min.The reaction was stirred for 1 hr and was then poured into a mixture ofice water and 10% potassium carbonate. The product was extracted withtwo portions of methylene chloride and each methylene chloride layer waswashed with a portion of brine. The methylene chloride layers werecombined, dried over sodium sulfate and evaporated. The residue waspurified with flash chromatography using ethyl acetate, then 2%triethylamine/10% methanol/88% ethyl acetate to afford 2.1 gm of thetitle compound as a white solid.

    ______________________________________                                        Analysis:       C.sub.30 H.sub.42 N.sub.4 O.sub.4                             ______________________________________                                        Calc:           C, 69.64; H, 7.92; N, 10.48                                   Found:          C, 69.62; H, 8.23; N, 10.46                                   ______________________________________                                    

EXAMPLE 20 S-(R*,S*)!-2- 4-(4-Methyl)piperazin-1-yl!carbonyl!phenoxy!-((3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide

WhenS-(R*,S*)!4-(((3,3-diethyl-1-((3,4-methylenedioxyphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoylchloride (3.1 mmol), prepared as in Example 11A, was reacted withN-methylpiperazine as in Example 19, there was obtained 1.75 gm of thetitle compound.

    ______________________________________                                        Analysis:       C.sub.31 H.sub.40 N.sub.4 O.sub.6                             ______________________________________                                        Calc:           C, 65.94; H, 7.14; N,  9.92                                   Found:          C, 65.80; H, 7.31; N, 10.05                                   ______________________________________                                    

EXAMPLE 21 S-(R*,S*)!2- 4-(4-Hydroxyethyl)piperazin-1-yl!carbonyl!phenoxy!-((3,3-diethyl-N-1-(methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide

WhenS-(R*,S*)!-4-(((3,3-diethyl-1-((4-methylphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoylchloride (3.8 mmol), prepared as in Example 11A, was reacted withN-(2-hydroxyethyl)piperazine (7.6 mmol) and diisopropylethylamine (3.8mmol) as in Example 19, there was obtained 2.1 gm of the title compound.

    ______________________________________                                        Analysis:       C.sub.32 H.sub.44 N.sub.4 O.sub.5                             ______________________________________                                        Calc:           C, 68.06; H, 7.85; N,  9.92                                   Found:          C, 67.88; H, 7.87; N, 10.17                                   ______________________________________                                    

EXAMPLE 22 S-(R*,S*)!2- 4-(4-Hydroxyethyl)piperazin-1-yl!carbonyl!phenoxy!-((3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide

WhenS-(R*,S*)!-4-(((3,3-diethyl-1-((3,4-methylenedioxyphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoylchloride (3.1 mmol), prepared as in Example 11A, was reacted withN-(2-hydroxyethyl)piperazine (6.2 mmol) and diisopropylethylamine (3.1mmol) as in Example 19, there was obtained 1.50 gm of the titlecompound.

    ______________________________________                                        Analysis:       C.sub.32 H.sub.42 N.sub.4 O.sub.7.1.5H2O                      ______________________________________                                        Calc:           C, 61.94; H, 6.89; N, 9.06                                    Found:          C, 61.95; H, 6.92; N, 8.96                                    ______________________________________                                    

EXAMPLE 23 S-(R*,S*)!-2- 4-(4-Cyclopropyl)piperazin-1-yl!carbonyl!phenoxy!-((3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide

To a solution ofS-(R*,S*)!-4-(((3,3-diethyl-1-((4-methylphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoylchloride (3.8 mmol), prepared as in Example 11A, in 50 ml of methylenechlorine was added N-(cyclopropyl)piperazine dihydrochloride (5.7 mmol)and then a solution of diisopropylethylamine (15.8 mmol) in 10 ml ofmethylene chloride was added over 5 min with ice-bath cooling. Thereaction was stirred for 1 hr at 0° C. and then poured into ice water.The product was extracted with two portions of methylene chloride andeach methylene chloride layer was washed with a portion of brine. Themethylene chloride layers were combined, dried over sodium sulfate andethyl acetate/50% hexanes, then 70% ethyl acetate/30% hexanes to afford2.1 gm of the title compound as a white solid.

    ______________________________________                                        Analysis:       C.sub.32 H.sub.42 N.sub.4 O.sub.4                             ______________________________________                                        Calc:           C, 70.69; H, 7.91; N, 9.99                                    Found:          C, 70.62; H, 8.04; N, 9.95                                    ______________________________________                                    

EXAMPLE 24 S-(R*,S*)!2- 4-(4-Cyclopropyl)piperazin-1-yl!carbonyl!phenoxy!-((3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide

WhenS-(R*,S*)!4-(((3,3-diethyl-1-((3,4-methylenedioxyphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoylchloride (3.1 mmol), prepared as in Example 11A, was reacted withN-(cyclopropyl)piperazine (4.6 mmol) and diisopropylethylamine (9.3mmol) as in Example 23, there was obtained 1.80 gm of the titlecompound.

    ______________________________________                                        Analysis:       C.sub.32 H.sub.42 N.sub.4 O.sub.7                             ______________________________________                                        Calc:           C, 67.10; H, 7.17; N, 9.49                                    Found:          C, 67.03; H, 7.31; N, 9.47                                    ______________________________________                                    

EXAMPLE 25 S-(R*,S*)!-2- 4-(4-Piperazin-1-yl)carbonyl!phenoxy!-((3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide

Step A:

S-R*,S*)!2- 4-(4-(t-Butoxycarbonyl))piperazin-1-yl!carbonyl!phenoxy!-((3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide

S-(R*,S*)!4-(((3,3-Diethyl-1-((4-methylphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoylchloride (0.4 mmol), prepared as in Example 11A, was reacted withN-(t-butoxycarbonyl)piperazine (0.6 mmol) and triethylamine (1.2 mmol)as in Example 23. The crude, title product so obtained was used directlyin the following Step B.

Step B:

S-R*,S*)!-2- 4- (Piperazin-1-yl)carbonyl!phenoxy!-((3,3-diethyl-N-1-(4-methylphenyl)butyl-1-4-oxo-1-azetidinecarboxamide

The product from Step A was dissolved in 0.5 ml of anisole and 2 ml ofcold TFA was added. The reaction was stirred at 0° C. for 1 hr and wasthen diluted with methylene chloride and evaporated. The residue wastaken up in methylene chloride, washed with 10% sodium carbonate andbrine, dried over sodium sulfate and concentrated. The residue waspurified by flash chromatography using 5, then 10% methanol/methylenechloride to afford 0.212 gm of title product.

    ______________________________________                                        Analysis:       C.sub.30 H.sub.40 N.sub.4 O.sub.5 .1H2O                       ______________________________________                                        Calc:           C, 66.89; H, 7.85; N, 10.40                                   Found:          C, 67.06; H, 7.55; N, 10.30                                   ______________________________________                                    

EXAMPLE 26 S-(R*,S*)!-2- 4-(4-Piperazin-1-yl)carbonyl!phenoxy!-((3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide

Step A:

S-R*,S*)!-2- 4-(4-Benzyloxycarbonyl)Piperazin-1-yl!carbonyl!phenoxy!-((3,3-diethyl-N-1-3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamid

WhenS-(R*,S*)!-4-(((3,3-diethyl-1-((3,4-methylenedioxyphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoylchloride (0.41 mmol), prepared as in Example 11A, was reacted withN-(benzyloxycarbonyl)piperazine (0.77 mmol) and diisopropylethylamine(1.6 mmol) as in Example 23, there was obtained 290 mg of the titlecompound.

Step B:

S-R*,S*)!2- 4- (Piperazin-1-yl)carbonyl!phenoxy!-((3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl-4-oxo-1-azetidinecarboxamide

A solution of 250 mg of material from Example 26, Step A in 10 ml ofethanol was hydrogenated at 40 p.s.i. over 50 mg of 10% Pd/C for 16 hrs.The reaction was filtered and evaporated. The residue was purified bypreparative TLC eluting with 2%

TEA/10% methanol/88% ethyl acetate to afford 150 mg of title product.

    ______________________________________                                        Analysis:       C.sub.30 H.sub.38 N.sub.4 O.sub.6.3H2O                        ______________________________________                                        Calc:           C, 59.59; H, 7.33; N, 9.29                                    Found:          C, 59.66; H, 7.65; N, 9.61                                    ______________________________________                                    

What is claimed is:
 1. A Method of treating an elastase mediated diseaseselected from the group consisting of emphysema, bronchial inflammation,chronic bronchitis, cystic fibrosis, and acute respiratory distresssyndrome in a patient having said disease comprising the administrationof a non-toxic therapeutically effective amount of a compound of Formula##STR34## when n and A are: n A14-morpholinyl, 2 1--N(CH₃)CH₂ CH₂N(CH₃)₂, 3 0--N(CH₃)CH₂ CH₂ N(CH₃)₂, 4 0--N(Et)₂, 5 0--N(CH₃)(n-Bu), 6 04-methyl-1-piperazinyl, 7 0--N(CH₃)CH₂ CH₂ N(CH₃)CH₂ Ph, 8 04-cyclopropyl-1-piperazinyl, 9 0 1-piperazinyl, 10 04-(2-hydroxyethyl)-1-piperazinyl, or 11 0 4-morpholinyl.
 2. A methodaccording to claim 1 wherein the compound is S-(R*,S*)!-2- 4-4-methylpiperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidine-carboxamide, or apharmaceutically acceptable salt thereof.
 3. A method of treating cysticfibrosis according to claim 2 wherein the compound is S-(R*,S*)!-2- 4-4-methylpiperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide,or a pharmaceutically acceptable salt thereof.
 4. A Method of treatingan elastase mediated disease selected from the group consisting ofemphysema, bronchial inflammation, chronic bronchitis, cystic fibrosis,and acute respiratory distress syndrome in a patient having said diseasecomprising the administration of a non-toxic therapeutically effectiveamount of a compound selected from(a) S-(R*,S*)!-2- 4-2-(dimethylamino)ethyl!methylamino!carbonyl!-phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidine-carboxamide, (b)S-(R*,S*)!-2- 4-2-(dimethylamino)ethyl!methylamino!carbonyl!-phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxy-phenyl)butyl!-4-oxo-1-azetidine-carboxamide, (c)S-(R*,S*)!-2- 4- 4-methylpiperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (d) S-(R*,S*)!-2-4- 4-methylpiperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxy-phenyl)butyl!-4-oxo-1-azetidine-carboxamide, (e)S-(R*,S*)!-2- 4-4-cyclopropylpiperazin-1-yl!-carbonyl!phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidine-carboxamide, (f)S-(R*,S*)!-2- 4-4-cyclopropylpiperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidine-carboxamide, (g)S-(R*,S*)!-2- 4- piperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (h) S-(R*,S*)!-2-4- piperazin-1-yl!carbonyl!-phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (i)S-(R*,S*)!-2- 4-((2-dimethylamino)ethyl)ethylamino!carbonyl!-phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (j) S-(R*,S*)!-2-4- ((2-diethylamino)ethyl)ethylamino!carbonyl!-phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (k) S-(R*,S*)!-2-4- (4-(2-hydroxyethyl))piperazin-1-yl!carbonyl!-phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (l) S-(R*,S*)!-2-4- (4-(2-hydroxyethyl))piperazin-1-yl!carbonyl!-phenoxy!-3,3-diethyl-N-1-(3,4,-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide, or (m)S-(R*,S*)!-2- 4-(4-(ethoxycarbonylmethyl))piperazin-1-yl!-carbonyl!phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)-butyl!-4-oxo-1-azetidinecarboxamide.
 5. Amethod of treating an elastase mediated disease selected from the groupconsisting of rheumatoid arthritis and osteoarthritis in a patienthaving said disease comprising the administration of a non-toxictherapeutically effective amount of a compound of Formula ##STR35##where n and A are:

    ______________________________________                                        n             A                                                               ______________________________________                                        1      1          4-morpholinyl,                                              2      1          --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2,           3      0          --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2,           4      0          --N(Et).sub.2,                                              5      0          --N(CH.sub.3)(n-Bu),                                        6      0          4-methyl-1-piperazinyl,                                     7      0          --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph,      8      0          4-cyclopropyl-1-piperazinyl,                                9      0          1-piperazinyl,                                              10     0          4-(2-hydroxyethyl)-1-piperazinyl, or                        11     0          4-morpholinyl.                                              ______________________________________                                    


6. A method according to claim 5 wherein the compound is S-(R*,S*)!-2-4- 4-methylpiperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide, or apharmaceutically acceptable salt thereof.
 7. A method of treating aelastase mediated disease selected from the group consisting ofrheumatoid arthritis and osteoarthritis in a patient having said diseasecomprising the administration of a non-toxic therapeutically effectiveamount of a compound selected from(a) S-(R*,S*)!-2- 4-2-(dimethylamino)ethyl!methylamino!carbonyl!-phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (b) S-(R*,S*)!-2-4- 2-(dimethylamino)ethyl!methylamino!carbonyl!-phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxy-phenyl)butyl!-4-oxo-1-azetidine-carboxamide, (c)S-(R*,S*)!-2- 4- 4-methylpiperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (d) S-(R*,S*)!-2-4- 4-methylpiperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxy-phenyl)butyl!-4-oxo-1-azetidine-carboxamide, (e)S-(R*,S*)!-2- 4-4-cyclopropylpiperazin-1-yl!-carbonyl!phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidine-carboxamide, (f) S-(R*,S*)-2-4- 4-cyclopropylpiperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (g)S-(R*,S*)!-2- 4- piperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, or (h)S-(R*,S*)!-2- 4- piperazin-1-yl!carbonyl!-phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (i)S-(R*,S*)!-2- 4-((2dimethylamino)ethyl)ethylamino!carbonyl!4-oxo-1-phenoxy!-3,3-diethyl-N-1(4-methylphenyl)butyl!- (j) S-(R*,S*)!-2- 4-((2-diethylamino)ethyl)ethylamino!carbonyl!-phenoxyl!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (k) S-(R*,S*)!-2-4- (4-(2-hydroxyethyl))piperazin-1-yl!carbonyl!-phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (l) S-(R*,S*)!-2-4- (4-(2-hydroxyethyl))piperazin-1-yl!carbonyl!-phenoxy!-3,3-diethyl-N-1-(3,4,-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide, or (m)S-(R*,S*)!-2- 4-(4-(ethoxycarbonylmethyl))piperazin-1-yl!-carbonyl!phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)-butyl!-4-oxo-1-azetidinecarboxamide. 8.Method of treating a disease selected from the group consisting ofglomerulonephritis, spondylitis, lupus, psoriasis, atherosclerosis,sepsis, septicemia, shock, myocardial infarction, reperfusion injury,and periodontitis in a patient in need of such treatment comprising theadministration therapeutically effective amount of a compound of Formula##STR36## when n and A are:

    ______________________________________                                        n             A                                                               ______________________________________                                        1      1          4-morpholinyl,                                              2      1          --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2,           3      0          --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2,           4      0          --N(Et).sub.2,                                              5      0          --N(CH.sub.3)(n-Bu),                                        6      0          4-methyl-1-piperazinyl,                                     7      0          --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph,      8      0          4-cyclopropyl-1-piperazinyl,                                9      0          1-piperazinyl,                                              10     0          4-(2-hydroxyethyl)-1-piperazinyl, or                        11     0          4-morpholinyl.                                              ______________________________________                                    


9. A method according to claim 8 wherein the compound is S-(R*,S*)!-2-4- 4-methylpiperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide, or apharmaceutically acceptable salt thereof.
 10. Method of treating adisease selected from the group consisting of glomerulonephritis,spondylitis, lupus, psoriasis, atherosclerosis, sepsis, septicemia,shock, myocardial infarction, reperfusion injury, and periodontitis in apatient in need of such treatment comprising the administrationtherapeutically effective amount of a compound selected from(a)S-(R*,S*)!-2- 4-2-(dimethylamino)ethyl!methylamino!carbonyl!-phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (b) S-(R*,S*)!-2-4- 2-(dimethylamino)ethyl!methylamino!carbonyl!-phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxy-phenyl)butyl!-4-oxo-1-azetidine-carboxamide, (c)S-(R*,S*)!-2- 4- 4-methylpiperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (d) S-(R*,S*)!-2-4- 4-methylpiperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxy-phenyl)butyl!-4-oxo-1-azetidine-carboxamide, (e)S-(R*,S*)!-2- 4-4-cyclopropylpiperazin-1-yl!-carbonyl!phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidine-carboxamide, (f)S-(R*,S*)!-2- 4-4-cyclopropylpiperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (g)S-(R*,S*)!-2- 4- piperazin-1-yl!carbonyl!phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, or (h)S-(R*,S*)!-2- 4- piperazin-1-yl!carbonyl!-phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (i)S-(R*,S*)!-2- 4-((2-dimethylamino)ethyl)ethylamino!carbonyl!-phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (j) S-(R*,S*)!-2-4- ((2-diethylamino)ethyl)ethylamino!carbonyl!-phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (k) S-(R*,S*)!-2-4- (4-(2-hydroxyethyl))piperazin-1-yl!carbonyl!-phenoxy!-3,3-diethyl-N-1-(4-methylphenyl)butyl!-4-oxo-1-azetidinecarboxamide, (l) S-(R*,S*)!-2-4- (4-(2-hydroxyethyl))piperazin-1-yl!carbonyl!-phenoxy!-3,3-diethyl-N-1-(3,4,-methylenedioxyphenyl)butyl!-4-oxo-1-azetidinecarboxamide, or (m)S-(R*,S*)!-2- 4-(4-(ethoxycarbonylmethyl))piperazin-1-yl!-carbonyl!phenoxy!-3,3-diethyl-N-1-(3,4-methylenedioxyphenyl)-butyl!-4-oxo-1-azetidinecarboxamide.